Inhibitors of influenza virus replication, application methods and uses thereof

ABSTRACT

The invention provides a novel class of compounds as inhibitors of influenza virus replication, preparation methods thereof, pharmaceutical compositions containing these compounds, and uses of these compounds and pharmaceutical compositions thereof in the treatment of influenza.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. national stage application of the International PatentApplication No. PCT/CN2016/109079, filed Dec. 8, 2016, which claimspriority to Chinese Patent Application No. 201510908329.2, filed Dec. 9,2015, both of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The invention belongs to the pharmaceutical field, specifically, itrelates to novel compounds used as inhibitors of influenza virusreplication, preparation methods thereof, pharmaceutical compositionscontaining these compounds, and uses of these compounds andpharmaceutical compositions thereof in the treatment of influenza. Morespecifically, the compounds of the invention can be used as inhibitorsof RNA polymerase of the influenza virus.

BACKGROUND

Influenza is an acute respiratory infectious disease and harmful tohuman health, which is caused by the influenza virus and characterizedby high prevalence, widespread, rapid propagation. Influenza virus cancause serious symptoms in the elderly and children with weaker immunesystems, and immunocompromised patients, such as pneumonia orcardiopulmonary failure. Influenza virus was first discovered by WilsonSmith, a British, who called influenza virus as H1N1. The H denoteshemagglutinin; the N denotes neuraminidase, and the numbers representdifferent types. Influenza virus has caused the global pandemic for manytimes since the discovery, and the outbreak of influenza virus happensevery decade or so, which causes enormous losses in worldwide. Influenzaspreads around the world in a yearly outbreak, resulting in about250,000 to 500,000 deaths, and about three to five million cases ofsevere illness, and a total of about 5% to 15% of people in worldwideare infected. Every time a pandemic was due to the emergence of newstrains in humans. Usually, these new strains are caused by the spreadof existing influenza virus from other animal species to humans

Influenza viruses are RNA viruses belong to the family oforthomyxoviridae, which belong to the genus of influenza virus.According to the differences of the virion nucleoprotein (NP) and matrixprotein (M) antigenic characteristics and genetic characteristics,influenza viruses are divided into three types: A, B and C. The threetypes of influenza viruses have similar biochemical and biologicalcharacteristics. The virus particle is 80-120 nanometers in diameter andusually roughly spherical, although filamentous forms can occur. Virusis constituted with three layers, and the inner layer is the viralnucleocapsid containing nucleoprotein (NP), P protein and RNA. NP is asoluble antigen (S antigen) with type specificity and antigenicstability. P protein (P1, P2, P3) may be polymerase required for RNAtranscription and replication. Middle viral envelope consists of alipoid layer and a layer of membrane protein (MP), MP has antigenicstability and type specificity. Outer layer is a radial tuber consistingof two different glycoprotein projections, i.e., hemagglutinin (H) andneuraminidase (N). H is a tool for viral absorption on sensitive cellsurface which can cause agglutination of erythrocyte, N is a tool forbreaking away from cell surface after the completing of virusreplication, which is capable of hydrolyzing mucus protein andN-acetylneuraminic acid that locates at the end of cell surface specificglycoprotein receptor. H and N both have variation characteristics, andonly have the strain specific antigen, the antibody of which has aprotective effect.

Influenzavirus A has one species, influenza A virus. Wild aquatic birdsare the natural hosts for a large variety of influenza A. Occasionally,viruses are transmitted to other species and may then cause devastatingoutbreaks in domestic poultry or give rise to human influenza pandemics.The type A virus is the most virulent human pathogen among the threeinfluenza types and cause the severest disease, and can be transmittedto other species and may then cause human influenza pandemic. Theinfluenza A virus can be subdivided into different serotypes based onthe antibody response to these viruses. The serotypes that have beenconfirmed in humans, ordered by the number of known human pandemicdeaths, are: H1N1, which caused Spanish Flu in 1918; H2N2, which causedAsian Flu in 1957; H3N2, which caused Hong Kong Flu in 1968; H5N1, whichcaused pandemic threats in the influenza season of 2007-2008; H7N7,which has unusual zoonotic potential; H1N2, endemic in humans and pigs;H9N2; H7N2; H7N3; and H10N7.

Influenzavirus B has one species, influenza B virus, which causes localepidemic influenza and can not cause the global influenza pandemic. Theonly animals known to be susceptible to influenza B infection are humansand the seal. This type of influenza mutates at a rate 2-3 times slowerthan type A and consequently is less genetically diverse, with only oneinfluenza B serotype. As a result of this lack of antigenic diversity, adegree of immunity to influenza B is usually acquired at an early age.However, influenza B mutates enough that lasting immunity is notpossible. This reduced rate of antigenic change, combined with itslimited host range (inhibiting cross species antigenic shift), ensuresthat pandemics of influenza B do not occur.

Influenzavirus C has one species, influenza C virus, which exists insporadic form, and usually only causes mild disease in children.Influenzavirus C usually can not cause influenza pandemic, and infecthumans and pigs.

Unusually for a virus, its genome is not a single piece of nucleic acid;instead, it contains seven or eight pieces of segmented negative-senseRNA. The genome of influenza A viruses encodes 11 proteins:hemagglutinin (H), neuraminidase (N), nucleoprotein (N), M1, M2, NS1,NS2 (NEP), PA, PB1 (polymerase basic 1), PB1-F2 and PB2. Hemagglutinin(H) and neuraminidase (N) are the two large glycoproteins on the outsideof the viral particles. HA is a lectin that mediates binding of thevirus to target cells and entry of the viral genome into the targetcell, while NA is involved in the release of progeny virus from infectedcells, by cleaving sugars that bind the mature viral particles. Thus,these proteins are targets for antiviral drugs. Furthermore, they areantigens to which antibodies can be raised. Influenza A viruses areclassified into subtypes based on antibody responses to H and N. Thesedifferent types of HA and NA form the basis of the H and N distinctionsin, for example, H5N1.

Vaccination and usage of antiviral drugs are important tools forresponding to influenza pandemic. Due to the high mutation rate of theflu virus antigen, the vaccine can't be produced in large scale beforeinfluenza pandemic. The two classes of antiviral drugs used againstinfluenza are M2 protein inhibitors (amantadine and rimantadine) andneuraminidase inhibitors (oseltamivir, zanamivir, peramivir andLaninamivir). However, the influenza viruses have developed drugresistance to all these drugs. Therefore, continuing demand for newanti-influenza treatment agent is existing.

Favipiravir, a new antiviral agent, having a new mechanism, has beenlaunched, which plays antiviral action by inhibiting RNA polymerase ofthe influenza virus to target the inhibition of viral gene replication,but the therapeutic effect and the drug resistance of influenza virusesstill need to be proved. Therefore, other compounds as anti-influenzaagents of this mechanism still needed to be researched.

SUMMARY OF THE INVENTION

The invention discloses a novel class of compounds used as inhibitors ofRNA polymerase of the influenza virus. These compounds and compositionsthereof can be used in the manufacture of a medicament for preventing,managing, treating or lessening virus infection in patients.

In one aspect, provided herein is a compound having Formula (I) or astereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, X, m and n are as defined herein.

In certain embodiments, each R¹ and R³ is independently H, F, Cl, Br,CN, NO₂, —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), OR^(b),—NR^(c)R^(d), R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄alkylene, 3- to 12-membered heterocyclyl, (3- to 12-memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to10-membered heteroaryl or (5- to 10-membered heteroaryl)-C₁₋₄ alkylene,and wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 10-membered heteroaryl and (5- to10-membered heteroaryl)-C₁₋₄ alkylene is independently unsubstituted orsubstituted with one, two, three or four substituents independentlyselected from F, Cl, Br, CN, OR^(b), —NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆haloalkyl, R^(b)O—C₁₋₄ alkylene or R^(d)R^(c)N—C₁₋₄ alkylene;

n is 0, 1, 2 or 3;

each R² is independently F, C₂₋₆ alkynyl, OR^(b), C₃₋₁₂ carbocyclyl,C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-membered heterocyclyl, (3- to12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 14-membered heteroaryl, (5- to 14-memberedheteroaryl)-C₁₋₄ alkylene; or two adjacent R², together with the atomsto which they are attached, form a C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring or or 5- to10-membered heteroaromatic ring, and wherein each of the C₂₋₆ alkynyl,C₃₋₁₂ carbocyclyl, C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 14-membered heteroaryl, (5- to14-membered heteroaryl)-C₁₋₄ alkylene, C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring and 5- to 10-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F;

each R′ is independently F, Cl, Br, CN, NO₂, oxo (═O), OR^(b),—NR^(c)R^(d), R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 3- to6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄ alkylene,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-membered heteroaryl or (5-to 6-membered heteroaryl)-C₁₋₄ alkylene, and wherein each of the C₁₋₁₀alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,3- to 6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-memberedheteroaryl and (5- to 6-membered heteroaryl)-C₁₋₄ alkylene isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, Br, CN, NO₂, OR^(b),—NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆ haloalkyl, R^(b)O—C₁₋₄ alkylene orR^(d)R^(c)N—C₁₋₄ alkylene;

m is 1 or 2;

X has one of the following sub-formulae:

wherein R⁴ is H or C₁₋₆ alkyl, and wherein the C₁₋₆ alkyl is optionallysubstituted with one, two, three, or four U;

each R⁵, R⁶, R⁷ and R⁸ is independently H or C₁₋₆ alkyl; or R⁵ and R⁶,together with the carbon atom to which they are attached, form a C₃₋₈cycloalkyl group, 3- to 6-membered heterocyclic ring, C₆₋₁₀ aromaticring or 5- to 10-membered heteroaromatic ring; or R⁷ and R⁸, togetherwith the nitrogen atom to which they are attached, form a 3- to6-membered heterocyclic ring or 5- to 10-membered heteroaromatic ring,and wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 3- to 6-memberedheterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, or four U;

W is a C₃₋₁₂ carbocyclic ring or 3- to 12-membered heterocyclic ring;

each V and V′ is independently a C₃₋₁₂ cycloalkane ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring;

each R^(w) is independently F, Cl, Br, CN, NO₂, oxo (═O), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e), —S(═O)₂NR^(c)C(═O)R^(a),—S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂ alkylene, OR^(b), —NR^(c)R^(d),R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂ alkylene, C₁₋₆ alkyl, 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl, and wherein eachof the C₁₋₆ alkyl, 5- to 6-membered heteroaryl or 5- to 6-memberedheterocyclyl is independently unsubstituted or substituted with one,two, three, or four U;

each U is independently F, Cl, Br, NO₂, CN, oxo (═O), N₃, OR^(b),—NR^(c)R^(d), C₁₋₆ alkyl or C₁₋₆ haloalkyl;

each s and t is independently 0, 1, 2 or 3;

p is 1, 2 or 3; and

each R^(a), R^(b), R^(c), R^(d) and R^(e) is independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkylene, 3- to 6-membered heterocyclyl, (3- to6-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 10-membered heteroaryl, (5- to 10-memberedheteroaryl)-C₁₋₄ alkylene; or R^(c) and R^(d), together with thenitrogen atom to which they are attached, form a 3- to 6-memberedheterocyclic ring, and wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 3- to6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄ alkylene,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 10-membered heteroaryl, (5-to 10-membered heteroaryl)-C₁₋₄ alkylene and 3- to 6-memberedheterocyclic ring is independently unsubstituted or substituted withone, two, three, or four substituents independently selected from F, Cl,CN, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy or C₁₋₆ alkylamino.

In other embodiments, the invention relates to a compound having Formula(II), or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, X, R′, n and q are as defined herein.

In other embodiments, A is a C₃₋₁₂ carbocyclic ring, 3- to 12-memberedheterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring; and

q is 0, 1, 2, 3, 4 or 5.

In other embodiments, each R¹ and R³ is independently H, F, Cl,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), OR^(b), —NR^(c)R^(d), C₁₋₃alkyl, C₃₋₆ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to6-membered heteroaryl, and wherein each of the C₁₋₃ alkyl, C₃₋₆cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-memberedheteroaryl is independently unsubstituted or substituted with one, two,three or four substituents independently selected from F, Cl, OR^(b),—NR^(c)R^(d), C₁₋₃ alkyl, C₁₋₃ haloalkyl or R^(b)O—C₁₋₂ alkylene.

In other embodiments, each R² is independently F, C₂₋₆ alkynyl, OR^(b),C₃₋₆ carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene; or two adjacent R², together withthe atoms to which they are attached, form a C₅₋₆ carbocyclic ring, 5-to 6-membered heterocyclic ring, benzene ring or 5- to 6-memberedheteroaromatic ring, and wherein each of the C₂₋₆ alkynyl, C₃₋₆carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene, C₅₋₆ carbocyclic ring, 5- to6-membered heterocyclic ring, benzene ring and 5- to 6-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F.

In other embodiments, each R′ is independently F, Cl, Br, CN, NO₂,OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)NR^(c)R^(d), C₁₋₉ alkyl, C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene or 5- to 6-membered heteroaryl, and wherein each ofthe C₁₋₉ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 5- to 6-memberedheterocyclyl, phenyl, phenyl-C₁₋₄ alkylene and 5- to 6-memberedheteroaryl is independently unsubstituted or substituted with one, two,three, or four substituents independently selected from F, Cl, Br, CN,NO₂, OR^(b), —NR^(c)R^(d), methyl, ethyl, n-propyl or i-propyl.

In other embodiments, each R^(a), R^(b), R^(c), R^(d) and R^(e) isindependently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 3- to6-membered heterocyclyl, phenyl, phenyl-C₁₋₂ alkylene; or R^(c) andR^(d), together with the nitrogen atom to which they are attached, forma 5- to 6-membered heterocyclic ring, and wherein each of methyl, ethyl,i-propyl, n-propyl, n-butyl, t-butyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 3- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene and 5- to 6-membered heterocyclic ring isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, CN, OH, NH₂, C₁₋₃ alkyl,C₁₋₃ haloalkyl or methoxy.

In other embodiments, X has one of the following sub-formulae:

wherein W, V, V′, R⁵, R⁶, R⁷, R⁸, R^(w) and s are as defined herein.

In other embodiments, W is a C₆₋₈ carbocyclic ring or 6- to 8-memberedheterocyclic ring.

In other embodiments, V is a C₃₋₈ cycloalkane ring, 3- to 8-memberedheterocyclic ring, benzene ring or 5- to 6-membered heteroaromatic ring.

In other embodiments, V′ is a C₃₋₈ cycloalkane ring, 3- to 8-memberedheterocyclic ring, benzene ring or 5- to 6-membered heteroaromatic ring.

In other embodiments, each R^(w) is independently F, Cl, Br, CN, NO₂,oxo (═O), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e),—S(═O)₂NR^(c)C(═O)R^(a), —S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂alkylene, OR^(b), —NR^(c)R^(d), R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂alkylene, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolylor pyrazolyl, and wherein each of methyl, ethyl, i-propyl, n-propyl,n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted orsubstituted with one, two, three, or four U.

In other embodiments, each U is independently F, Cl, Br, CF₃, NO₂, CN,oxo (═O), N₃, OR^(b), —NR^(c)R^(d), methyl, ethyl, i-propyl, n-propyl,n-butyl or t-butyl.

In other embodiments, A is a C₅₋₆ carbocyclic ring, 5- to 6-memberedheterocyclic ring, benzene ring, naphthalene ring or 5- to 6-memberedheteroaromatic ring.

In other embodiments, each R² is independently F, ethynyl, propynyl,OR^(b), C₃₋₆ carbocyclyl, 5- to 6-membered heterocyclyl, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl, pyrrolyl, pyridyl,pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl,pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl,isoquinolyl, phenoxthinyl,

and wherein each ethynyl, propynyl, C₃₋₆ carbocyclyl, 5- to 6-memberedheterocyclyl, phenyl, naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl,benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl,quinolyl, isoquinolyl, phenoxthinyl,

is independently unsubstituted or substituted with one, two, three, fouror five R′, with the proviso that when m is 1, R² is not F.

In other embodiments, X has one of the following sub-formulae:

wherein R^(w), s and V′ are as defined herein.

In other embodiments, A is a C₅₋₆ carbocyclic ring, 5- to 6-memberedheterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole,pyridine, pyrazole, imidazole, benzoimidazole, triazole, tetrazole,oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene, benzothiphene,pyrazine, pyridazine, pyrimidine, indole, purine, quinoline orisoquinoline.

In other embodiments, the invention relates to a compound having Formula(III) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(IV) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(V) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VI) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VII) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n, s, V′ and R are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VIII) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q, s, V′ and R^(w) are as defined herein.

In one aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein.

In certain embodiments, the pharmaceutical composition provided hereinfurther comprises a pharmaceutically acceptable carrier, adjuvant,vehicle or a combination thereof.

In certain embodiments, the pharmaceutical composition provided hereinfurther comprises one or more therapeutic agents.

In other embodiments, the therapeutic agent disclosed herein is ananti-influenza virus agent or anti-influenza virus vaccine.

In other embodiments, the pharmaceutical composition is in the form ofliquid, solid, semi-solid, gel or spray.

In other embodiments, the pharmaceutical composition disclosed herein,wherein the therapeutic agent is amantadine, rimantadine, oseltamivir,zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate,favipiravir, arbidol, ribavirin, stachyflin, ingavirin, fludase, CAS no.1422050-75-6, JNJ-872, AL-794, an influenza vaccine (FluMistQuadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax®or FluBlok®) or a combination thereof.

In another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing, managing, treating or lessening a disorder ordisease caused by virus infection in a patient.

In certain embodiments, the virus infection disclosed herein isinfluenza virus infection.

In another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for inhibiting RNA polymerase of the influenza virus.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in preventing, managing, treatingor lessening a disorder or disease caused by virus infection.

In certain embodiments, the virus infection disclosed herein isinfluenza virus infection.

In another aspect, provided herein is the compound or the pharmaceuticalcomposition disclosed herein for use in inhibiting RNA polymerase ofinfluenza virus.

In another aspect, provided herein is a method of preventing, managing,treating or lessening a disorder or disease caused by virus infection ina patient, comprising administering to the patient a therapeuticallyeffective amount of the compound or the pharmaceutical compositiondisclosed herein.

In certain embodiments, the virus infection disclosed herein isinfluenza virus infection.

In another aspect, provided herein is a method of inhibiting RNApolymerase of the an influenza virus in a patient, comprisingadministering to the patient a therapeutically effective amount of thecompound or the pharmaceutical composition disclosed herein.

Unless otherwise stated, all stereoisomers, geometric isomers,tautomers, solvates, hydrates, metabolites, salts and pharmaceuticallyacceptable prodrugs of the compounds disclosed herein are within thescope of the invention.

In one embodiment, the salt is a pharmaceutically acceptable salt. Thephrase “pharmaceutically acceptable” refers to that the substance orcomposition must be chemically and/or toxicologically compatible withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

In another embodiment, the salts are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of the invention and/or for separatingenantiomers of compounds of the invention.

Furthermore, the compounds disclosed herein, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the presentinvention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.

In another embodiment, the compound disclosed herein may contain severalasymmetric centers and therefore exist in the form of racemic mixturegenerally described. Furthermore, it is intended that all racemicmixture, parts of the racemic mixture, and enantiomer and diastereomerspurified by separation form part of the present invention.

The compounds disclosed herein may exists in the form of possibleisomers, including rotamers, atropisomers, tautomer or a mixturethereof. It is intended that mixtures of isomers, including rotamers,atropisomers, tautomers, parts of the mixtures of isomers, rotamers,atropisomers, tautomers, and the isomers, including rotamers,atropisomers, tautomer purified by separation form part of the presentinvention.

In another aspect, the compounds of the invention include isotopicallyenriched compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present.

In other aspect, provided herein is a method of preparing, separating orpurifying the compound of Formula (I).

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications, and equivalents which may be includedwithin the scope of the present invention as defined by the claims. Oneskilled in the art will recognize many methods and materials similar orequivalent to those described herein, which could be used in thepractice of the present invention. The present invention is in no waylimited to the methods and materials described herein. In the event thatone or more of the incorporated literature, patents, and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall be applied unlessotherwise indicated. For purposes disclosed herein, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, and the Handbook of Chemistry and Physics, 75 thEd. 1994. Additionally, general principles of organic chemistry aredescribed in Thomas Sorrell et al., “Organic Chemistry”, UniversityScience Books, Sausalito: 1999, and Michael B. Smith et al., “March'sAdvanced Organic Chemistry”, John Wiley & Sons, New York: 2007, all ofwhich are incorporated herein by reference in their entireties.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. The subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In other embodiments, the subject is a human.

The term “subject” can be used interchangeably with “patient” in theinvention. The term “subject” and “patient” refer to animals (eg., birdssuch as chicken, quail or turkey, or mammals), specially mammalsincluding non-primates (eg., cattle, pigs, horses, sheep, rabbits,guinea pigs, rats, dogs, cats and mice) and primates (eg., monkeys,chimpanzees and humans), more specially humans. In some embodiments, thesubject is a non-human animal, such as livestock (eg., horses, cattle,pigs or sheep) or pet (eg., dogs, cats, guinea pigs or rabbits). Inother some embodiments, the “patient” refers to a human.

Any formula given herein is also intended to represent isotopicallyunenriched forms as well as isotopically enriched forms of thecompounds. Isotopically enriched compounds have structures depicted bythe formulas given herein except that one or more atoms are replaced byan atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O, ¹⁷O,³¹P, ³²P, ³⁶S, ¹⁸F and ³⁷Cl, respectively.

The compounds disclosed herein containing isotopes described above orother atom isotopes and pharmaceutical salts thereof are included withinthe scope of the present invention. Certain isotopically-labeledcompounds of the present invention, for example those into whichradioactive isotopes such as ³H or ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Because of easypreparation and detection, isotopes such as tritiated, i.e., ³H, andcarbon-14, i.e., ¹⁴C are preferred. Further, substitution with heavierisotopes, particularly deuterium (i.e., ²H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. Therefore, the heavier isotopes may bepreferred in somewhere.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds disclosed herein may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds disclosedherein, including, but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. A specific stereoisomer may be referred to as anenantiomer, and a mixture of such stereoisomers is called anenantiomeric mixture. A specific stereoisomer is referred to as anenantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

The compounds disclosed herein may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds disclosed herein,including but not limited to, diastereomers, enantiomers, atropisomersand geometric (conformational) isomers as well as mixtures thereof suchas racemic mixtures, form part of the present invention.

Unless otherwise specified, the Formula described herein also containall the isomers thereof (such as, enantiomers, diastereomers,atropisomers and geometric (conformational) isomers; such as all (R)-and (S)-isomers, (Z) and (E) isomers around the double bond, (Z) and (E)conformational isomers. Therefore, single stereochemical isomers as wellas enantiomeric, diastereomeric, or geometric mixtures of the presentcompounds are within the scope disclosed herein.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Where tautomerization is possible (e.g., in solution), a chemicalequilibrium of tautomers can be reached. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. The specific example ofphenol-keto tautomerisms is pyridin-4-ol and pyridin-4(1H)-onetautomerism. Unless otherwise stated, all tautomeric forms of thecompounds disclosed herein are within the scope of the invention.

An “N-oxide” refers to one or more than one nitrogen atoms oxidised toform an N-oxide, where a compound contains several amine functions.Particular examples of N-oxides are the N-oxides of a tertiary amine ora nitrogen atom of a nitrogen-containing heterocycle. N-oxides can beformed by treatment of the corresponding amine with an oxidizing agentsuch as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid)(See, Advanced Organic Chemistry, by Jerry March, 4th Edition, WileyInterscience, pages). More particularly, N-oxides can be made by theprocedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which theamine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), forexample, in an inert solvent such as dichloromethane.

The term “solvate” refers to an association or complex of one or moresolvent molecules and a compound disclosed herein. Some non-limitingexamples of solvents that form solvates include water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid andethanolamine. The term “hydrate” refers to the complex where the solventmolecule is water.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. The metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from oxidation, reduction, hydrolysis,amidation, deamidation, esterification, deesterification, enzymecleavage, and the like, of the administered compound. Accordingly, theinvention includes metabolites of compounds disclosed herein, includingmetabolites produced by contacting a compound disclosed herein with amammal for a sufficient time period.

A “pharmaceutically acceptable salts” refers to organic or inorganicsalts of a compound disclosed herein. Pharmaceutically acceptable saltsare well known in the art. For example, S. M. Berge et al., describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66: 1-19, which is incorporated herein by reference.Some non-limiting examples of pharmaceutically acceptable and nontoxicsalts include salts of an amino group formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acidand perchloric acid or with organic acids such as acetic acid, oxalicacid, maleic acid, tartaric acid, citric acid, succinic acid and malonicacid or by using other methods used in the art such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphanic acid salt, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate,valerate salts, and the like. Salts derived from appropriate basesinclude alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄salts. This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroilsoluble or dispersable products may be obtained by suchquaternization. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C₁₋₈ sulfonate or aryl sulfonate.

The term “prodrug” refers to a compound that is transformed in vivo intoa compound of Formula (I). Such a transformation can be affected, forexample, by hydrolysis of the prodrug form in blood or enzymatictransformation to the parent form in blood or tissue. Prodrugs of thecompounds disclosed herein may be, for example, esters. Some commonesters which have been utilized as prodrugs are phenyl esters, aliphatic(C₁₋₂₄) esters, acyloxymethyl esters, carbonates, carbamates and aminoacid esters. For example, a compound disclosed herein that contains ahydroxy group may be acylated at this position in its prodrug form.Other prodrug forms include phosphates, such as, those phosphatecompounds derived from the phosphonation of a hydroxy group on theparent compound. A thorough discussion of prodrugs is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, J. Rautio et al., Prodrugs: Design and ClinicalApplications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J.Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal ofMedicinal Chemistry, 2008, 51, 2328-2345, all of which are incorporatedherein by reference in their entireties.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be present in racemic or enantiomerically enriched,for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. If the compound contains a double bond,the substituent may be cis-(Z) or trans-(E) configuration.

Therefore, as the invention described, the compound disclosed herein mayexist in the form of any possible isomer, such as rotational isomer,atropisomer, tautomer, or a mixture thereof, i.e., substantially puregeometric (cis- or trans-) isomer, diastereoisomer, optical isomer(enantiomer), racemate or a mixture thereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric isomers, optical isomers, diastereoisomers,racemate, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by methods known to those skilled inthe art, e.g., by separation of the diastereomeric salts thereof.Racemic products can also be resolved by chiral chromatography, e.g.,high performance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, U K, 2012);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutionsp. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.1972).

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, such as are illustratedgenerally below, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted”. The term “optional” or “optionally”refers to that a subsequently described event or circumstance may butneed not occur, and that the description includes instances where theevent or circumstance occurs and instances in which it does not. Ingeneral, whenever the term “optionally” is or is not before the term“substituted”, it refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position. Substituentsdescribed herein may be, but are not limited to, F, Cl, Br, CN, N₃, OH,NH₂, NO₂, oxo (═O), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),—S(═O)₂R^(e), —S(═O)₂NR^(c)C(═O)R^(a), —S(═O)₂NR^(c)R^(d),(R^(b)O)₂P(═O)—C₀₋₂ alkylene, OR^(b), —NR^(c)R^(d), R^(b)O—C₁₋₄alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆ alkyl, C₁₋₆ aliphatic radical,C₁₋₆ halolkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 14-membered heteroaryl or (5- to14-membered heteroaryl)-C₁₋₄ alkylene, and wherein R^(a), R^(b), R^(c),R^(d) and R^(e) are as defined herein.

Furthermore, what need to be explained is that the phrase “each . . . isindependently” and “each (of) . . . and . . . is independently”, unlessotherwise stated, should be broadly understood. The specific optionsexpressed by the same symbol are independent of each other in differentgroups; or the specific options expressed by the same symbol areindependent of each other in same groups.

At various places in the present specification, substituents ofcompounds disclosed herein are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification, linking substituents aredescribed. Where the structure clearly requires a linking group, theMarkush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “alkyl” or “alkyl group” refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms.Unless otherwise specified, the alkyl group contains 1-20 carbon atoms.In some embodiments, the alkyl group contains 1-10 carbon atoms. Inother embodiments, the alkyl group contains 1-9 carbon atoms. In otherembodiments, the alkyl group contains 1-8 carbon atoms. In otherembodiments, the alkyl group contains 1-6 carbon atoms. In still otherembodiments, the alkyl group contains 1-4 carbon atoms. In yet otherembodiments, the alkyl group contains 1-3 carbon atoms.

Some non-limiting examples of the alkyl group include, methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), n-propyl (n-Pr, —CH₂CH₂CH₃), isopropyl(i-Pr, —CH(CH₃)₂), n-butyl (n-Bu, —CH₂CH₂CH₂CH₃), isobutyl (i-Bu,—CH₂CH(CH₃)₂), sec-butyl (s-Bu, —CH(CH₃)CH₂CH₃), tert-butyl (t-Bu,—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, n-heptyl and n-octyl, etc.Wherein the alkyl group can be independently unsubstituted orsubstituted with one or more substitutents described herein.

The term “alkyl” or the prefix “alk-” is inclusive of both straightchain and branched saturated carbon chain.

The term “alkylene” refers to a saturated divalent hydrocarbon groupderived from a straight or branched chain saturated hydrocarbon by theremoval of two hydrogen atoms. Unless otherwise stated, the alkylenegroup contains 1-10 carbon atoms. In other embodiments, the alkylenegroup contains 1-6 carbon atoms. In still other embodiments, thealkylene group contains 1-4 carbon atoms. In yet other embodiments, thealkylene group contains 1-2 carbon atoms. Such alkylene group isexemplified by methylene (—CH₂—), ethylene (—CH₂CH₂—), isopropylene(—CH(CH₃)CH₂—), and the like. Wherein the alkylene group may beindependently unsubstituted or substituted with one or moresubstitutents described herein.

The term “alkenyl” refers to a linear or branched chain monovalenthydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or2 to 6 carbon atoms, or 2 to 4 carbon atoms, with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be independently unsubstituted or substituted withone or more substituents described herein, and includes radicals having“cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples of the alkenyl group include, but are not limitedto, vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like.

The term “alkynyl” refers to a linear or branched chain monovalenthydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or2 to 6 carbon atoms, or 2 to 4 carbon atoms, with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical is independently unsubstituted or substituted with one or moresubstituents described herein. Examples of alkynyl group include, butare not limited to, acetenyl (—C≡CH), propargyl (—CH₂C≡CH), 1-propynyl(—C≡C—CH₃), and the like.

The term “alkoxy” refers to an alkyl group, as previously defined,attached to the parent molecular moiety via an oxygen atom. Unlessotherwise specified, the alkoxy group contains 1-20 carbon atoms. Insome embodiments, the alkoxy group contains 1-10 carbon atoms. In otherembodiments, the alkoxy group contains 1-8 carbon atoms. In still otherembodiments, the alkoxy group contains 1-6 carbon atoms. In yet otherembodiments, the alkoxy group contains 1-4 carbon atoms. And in stillyet other embodiments, the alkoxy group contains 1-3 carbon atoms.

Some non-limiting examples of the alkoxy group include, methoxy (MeO,—OCH₃), ethoxy (EtO, —OCH₂CH₃), 1-propoxy (n-PrO, n-propoxy,—OCH₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, —OCH(CH₃)₂), 1-butoxy (n-BuO,n-butoxy, —OCH₂CH₂CH₂CH₃), 2-methyl-1-propoxy (i-BuO, i-butoxy,—OCH₂CH(CH₃)₂), 2-butoxy (s-BuO, s-butoxy, —OCH(CH₃)CH₂CH₃),2-methyl-2-propoxy (t-BuO, t-butoxy, —OC(CH₃)₃), 1-pentoxy (n-pentoxy,—OCH₂CH₂CH₂CH₂CH₃), 2-pentoxy (—OCH(CH₃)CH₂CH₂CH₃), 3-pentoxy(—OCH(CH₂CH₃)₂), 2-methyl-2-butoxy (—OC(CH₃)₂CH₂CH₃), 3-methyl-2-butoxy(—OCH(CH₃)CH(CH₃)₂), 3-methyl-1-butoxy (—OCH₂CH₂CH(CH₃)₂),2-methyl-1-butoxy (—OCH₂CH(CH₃)CH₂CH₃), and the like. Wherein the alkoxygroup is independently unsubstituted or substituted with one or moresubstitutents disclosed herein.

The terms “haloalkyl”, “haloalkenyl” or “haloalkoxy” refer to alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. Some non-limiting examples of “haloalkyl”, “haloalkenyl”or “haloalkoxy” groups include trifluoromethyl, trifluoromethoxy, andthe like.

The term “carbocycle”, “carbocyclyl”, “carbocyclic” or “carbocyclicring” used interchangeably herein refers to a ring having 3 to 14 ringcarbon atoms, which is saturated or contains one or more units ofunsaturation. In some embodiments, the number of carbon atom is 3 to 12;in other embodiments, the number of carbon atom is 3 to 10; in otherembodiments, the number of carbon atom is 3 to 8; in other embodiments,the number of carbon atom is 5 to 6; in other embodiments, the number ofcarbon atom is 6 to 8. The “carbocyclyl” includes a monocyclic,bicyclic, or polycyclic fused ring, spiro ring or bridged ring system,and a polycyclic ring system containing one carbocyclic ring fused withone or more non-aromatic carbocyclic ring or heterocyclic ring, or oneor more aromatic ring, or a combination thereof, wherein the linkedgroup or point exists on carbocyclic ring. The bicyclic carbocyclylgroups includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyland spiro bicyclic carbocyclyl group, and fused bicyclic system containstwo rings which share two adjacent ring atoms. Bridged bicyclic groupcontains two rings which share three or four adjacent ring atoms. Spirobicyclic system contains two ring which share one ring atom. Somenon-limiting examples of the carbocyclyl group include cycloalkyl,cycloalkenyl and cycloalkynyl. Further non-limiting examples ofcarbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like. Bridged bicyclic carbocyclylgroup includes, but are not limited to, bicyclo[2.2.2]octyl,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, and thelike.

The term “cycloalkyl” refers to a saturated ring having 3 to 12 ringcarbon atoms as a monocyclic, bicyclic, or tricyclic ring system, whichhas one or more attachments attaching to the rest of the molecule. Insome embodiments, the cycloalkyl group contains 3 to 10 ring carbonatoms. In other embodiments, the cycloalkyl group contains 3 to 8 ringcarbon atoms. In still other embodiments, the cycloalkyl group contains3 to 6 ring carbon atoms. In yet other embodiments, the cycloalkyl groupcontains 5 to 6 ring carbon atoms. The cycloalkyl radical isindependently unsubstituted or substituted with one or more substituentsdescribed herein.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic ring” as usedinterchangeably herein refers to a saturated or partially unsaturatednon-aromatic monocyclic, bicyclic or tricyclic ring containing 3-12 ringatoms of which at least one ring atom is selected from nitrogen, sulfurand oxygen, and of which may has one ore more attachments attached tothe rest of the molecule. The term “heterocyclyl” includes a monocyclic,bicyclic, or polycyclic fused, spiro, bridged heterocyclic ring system,and a polycyclic ring system containing one heterocyclic ring fused withone or more non-aromatic carbocyclic ring or heterocyclic ring, or oneor more aromatic ring, or a combination thereof, wherein the linkedgroup or attachment exists on heterocyclic ring. Biheterocyclyl radicalincludes bridged biheterocyclyl, fused biheterocyclyl and spirobiheterocyclyl. Unless otherwise specified, the heterocyclyl group maybe carbon or nitrogen linked, and a —CH₂— group can be optionallyreplaced by a —C(═O)— group. In which, the sulfur can be optionallyoxygenized to S-oxide and the nitrogen can be optionally oxygenized toN-oxide. In some embodiments, the heterocyclyl group is a 3- to8-membered mono- or bicyclic heterocyclyl group; in other embodiments,the heterocyclyl group is a 3- to 6-membered mono- or bicyclicheterocyclyl group; in other embodiments, the heterocyclyl group is a 6-to 8-membered mono- or bicyclic heterocyclyl group; in otherembodiments, the heterocyclyl group is a 5- to 6-membered heterocyclylgroup; in other embodiments, the heterocyclyl group is a 4-memberedheterocyclyl group; in other embodiments, the heterocyclyl group is a5-membered heterocyclyl group; in other embodiments, the heterocyclylgroup is a 6-membered heterocyclyl group; in other embodiments, theheterocyclyl group is a 7-membered heterocyclyl group; in otherembodiments, the heterocyclyl group is a 8-membered heterocyclyl group.

Some non-limiting examples of the heterocyclyl group include oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl,3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl,2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl,homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl,1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Some non-limitingexamples of heterocyclyl wherein —CH₂— group is replaced by —C(═O)—moiety include 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl,2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedione-yl. Somenon-limiting examples of heterocyclyl wherein the ring sulfur atom isoxidized is sulfolanyl and 1,1-dioxo-thiomorpholinyl. Some non-limitingexamples of the bridged heterocyclyl group include,2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl,3-azabicyclo[3.2.1]octyl, and the like. The heterocyclyl group may beoptionally substituted with one or more substituents disclosed herein.

The term “bridged” refers to a bond, an atom or an unbranched atomschain connecting two different parts of a molecule. The two atoms(usually but not always two tertiary carbon atoms) linked by the bridgedenotes “bridgeheads”.

The term “spiro” refers to a ring system containing one atom that is theonly one shared atom (usually a quaternary carbon) between two rings.

The term “n-membered”, where n is an integer typically described as thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidyl is an example of6-membered heterocyclyl and 1,2,3,4-tetrahydro-naphthyl group is anexample of a 10-membered carbocyclyl group.

The term “heteroatom” refers to oxygen (O), sulfur (S), nitrogen (N),phosphorus (P) and silicon (Si), including any oxidized form ofnitrogen, sulfur, or phosphorus; the quaternized form of any basicnitrogen; or a substitutable nitrogen of a heterocyclic ring, forexample, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR (as in N-substituted pyrrolidinyl).

The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), oriodo (I).

The term “azido” or “N₃” refers to an azide moiety. This radical may beattached, for example, to a methyl group to form azidomethane (methylazide, MeN₃); or attached to a phenyl group to form phenyl azide (PhN₃).

The term “aryl” used alone or as a great part of “arylalkyl”,“arylalkoxy”, refers to monocyclic, bicyclic and tricyclic carbocyclicring systems having a total of six to fourteen ring members, or six totwelve ring members, or six to ten ring members, wherein at least onering in the system is aromatic, wherein each ring in the system contains3 to 7 ring members and that has a single point or multipoint ofattachment to the rest of the molecule. The term “aryl” may be usedinterchangeably with the term “aryl ring” or “aromatic ring”. Somenon-limiting examples of the aryl group include phenyl, naphthyl andanthryl. The aryl group may be optionally unsubstituted or substitutedwith one or more substituents disclosed herein.

The term “heteroaryl” used alone or as a great part of “heteroarylalkyl”or “heteroarylalkoxy”, refers to monocyclic, bicyclic and tricyclic ringsystems having a total of five to fourteen ring members, or five totwelve ring members, or five to ten ring members, or five to six ringmembers, wherein at least one ring in the system is aromatic, and inwhich at least one ring member is selected from heteroatom, and whereineach ring in the system contains 5 to 7 ring members and that has asingle point or multipoint of attachment to the rest of the molecule.Unless otherwise specified, the heteroaryl group may be carbon ornitrogen linked, and a —CH₂— group can be optionally replaced by a—C(═O)— group. In which, the sulfur can be optionally oxygenized toS-oxide and the nitrogen can be optionally oxygenized to N-oxide. Theterm “heteroaryl” and “heteroaromatic ring” or “heteroaromatic compound”can be used interchangeably herein. In one embodiment, the heteroarylgroup is a 5- to 12-membered heteroaryl comprising 1, 2, 3 or 4heteroatoms independently selected from O, S and N. In anotherembodiment, the heteroaryl group is a 5- to 10-membered heteroarylcomprising 1, 2, 3 or 4 heteroatoms independently selected from O, S andN. In another embodiment, the heteroaryl group is a 5- to 6-memberedheteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selectedfrom O, S and N. In another embodiment, the heteroaryl group is a 5membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independentlyselected from O, S and N. In another embodiment, the heteroaryl group isa 6 membered heteroaryl comprising 1, 2, 3 or 4 heteroatomsindependently selected from O, S and N.

Some non-limiting examples of the heteroaryl group include the followingmonocyclic ring, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl,4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5H-tetrazolyl,2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl,4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl and 1,2,3-triazolyl), 2-thienyl,3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl,1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the followingbicycles, but are not limited to: benzimidazolyl, benzofuryl,benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g.,2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), oxathianyl,

The heteroaryl group is optionally substituted with one or moresubstituents disclosed herein.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, refer to —CO₂H. The term “carbonyl”,whether used alone or with other terms, such as “aminocarbonyl”,“acyloxy”, denotes —(C═O)—.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”wherein the amino groups are independently substituted with one alkylradical or two alkyl radicals, respectively. In some embodiments, thealkylamino group is a lower alkylamino group having one or two C₁₋₆alkyl groups attached to nitrogen atom. In other embodiments, thealkylamino group is a C₁₋₃ lower alkylamino group. Suitable alkylaminoradical may be monoalkylamino or dialkylamino. Examples of thealkylamino radical include, but are not limited to, N-methylamino,N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

The term “arylamino” refers to an amino group substituted with one ortwo aryl groups. Some non-limiting examples of such group includedN-phenylamino. In some embodiments, the aryl group of the arylamino maybe further substituted.

The term “aminoalkyl” refers to a C₁₋₁₀ linear or branched-chain alkylgroup substituted with one or more amino groups. In some embodiments,the aminoalkyl is a C₁₋₆ lower aminoalkyl substituted with one or moreamino groups. Some non-limiting examples of the aminoalkyl group includeaminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system represents substitution of substituents atany substitutable position on the rings, and wherein the ring systemincludes mono-, bi- or polycyclic ring system. For example, formula arepresents substitution of substituents at any substitutable position onthe bicyclic ring system of ring A and ring B, i.e., formula b-1 toformula b-8:

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system represents the bond can attach to the restof the molecule at any attachable position on the rings. For example,formula c represents substitution of substituents at any substitutableposition on the rings, i.e., formula d-1 and formula d-2.

The term “unsaturated” refers to a moiety having one or more units ofunsaturation.

The term “comprising” or “comprise” is meant to be open ended, includingthe indicated component but not excluding other elements.

As described herein, the term “pharmaceutically acceptable carrier”includes any solvents, dispersion media, coating agents, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, salt, drug stabilizers, binders, excipients,dispersants, lubricants, sweetening agents, flavoring agents, coloringagents, or a combination thereof, all of which are well known to theskilled in the art. (e.g., Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329, all of which areincorporated herein by reference). Except any conventional carrier isincompatible with the active ingredient, the pharmaceutically acceptablecarriers are effectively used in the treatment or pharmaceuticalcompositions.

As used herein, the term “inhibition of the replication of influenzaviruses” includes both the reduction in the amount of virus replication(e.g., the reduction by at least 10%) and the complete arrest of virusreplication (i.e., 100% reduction in the amount of virus replication).In some embodiments, the replication of influenza viruses are inhibitedby at least 50%, at least 65%, at least 75%, at least 85%, at least 90%,or at least 95%.

As used herein, an “effective amount” refers to an amount sufficient toelicit the desired biological response. In the present invention, thedesired biological response is to inhibit the replication of influenzavirus, to reduce the amount of influenza viruses or to reduce orameliorate the severity, duration, progression, or onset of a influenzavirus infection, prevent the advancement of an influenza virusinfection, prevent the recurrence, development, onset or progression ofa symptom associated with an influenza virus infection, or enhance orimprove the prophylactic or therapeutic effect(s) of another therapyused against influenza infections. The precise amount of compoundadministered to a subject will depend on the mode of administration, thetype and severity of the infection and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When co-administered with otheranti viral agents, e.g., when co-administered with an anti-influenzamedication, an “effective amount” of the second agent will depend on thetype of drug used. Suitable dosages are known for approved agents andcan be adjusted by the skilled artisan according to the condition of thesubject, the type of condition(s) being treated and the amount of acompound described herein being used. In cases where no amount isexpressly noted, an effective amount should be assumed. For example,compounds described herein can be administered to a subject in a dosagerange from between approximately 0.01 to 100 mg/kg body weight/day fortherapeutic or prophylactic treatment.

As used herein, the terms “treat”, “treatment” and “treating” refer toboth therapeutic and prophylactic treatments. For example, therapeutictreatments includes the reduction or amelioration of the progression,severity and/or duration of influenza viruses mediated conditions, orthe amelioration of one or more symptoms (specifically, one or morediscernible symptoms) of influenza viruses mediated conditions,resulting from the administration of one or more therapies (e.g., one ormore therapeutic agents such as a compound or composition of theinvention). In specific embodiments, the therapeutic treatment includesthe amelioration of at least one measurable physical parameter of aninfluenza virus mediated condition. In other embodiments the therapeutictreatment includes the inhibition of the progression of an influenzavirus mediated condition, either physically by, e.g., stabilization of adiscernible symptom, physiologically by, e.g., stabilization of aphysical parameter, or both. In other embodiments the therapeutictreatment includes the reduction or stabilization of influenza virusesmediated infections. Antiviral drugs can be used in the communitysetting to treat people who already have influenza to reduce theseverity of symptoms and reduce the number of days that they are sick.

The term “protecting group” or “PG” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting with other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxy-carbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and9-fluorenylmethylenoxy-carbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy-methyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)-ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF COMPOUNDS OF THE INVENTION

The invention discloses novel compounds used as inhibitors of influenzavirus replication and influenza virus RNA polymerase. These compoundsand compositions thereof can be used as therapeutic agents forpreventing, managing, treating or lessening virus infection in patients.

In one aspect, provided herein is a compound having Formula (I) or astereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug

wherein R¹, R², R³, X, m and n are as defined herein.

In certain embodiments, each R¹ and R³ is independently H, F, Cl, Br,CN, NO₂, —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), OR^(b),—NR^(c)R^(d), R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄alkylene, 3- to 12-membered heterocyclyl, (3- to 12-memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to10-membered heteroaryl or (5- to 10-membered heteroaryl)-C₁₋₄ alkylene,and wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 10-membered heteroaryl and (5- to10-membered heteroaryl)-C₁₋₄ alkylene is independently unsubstituted orsubstituted with one, two, three or four substituents independentlyselected from F, Cl, Br, CN, OR^(b), —NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆haloalkyl, R^(b)O—C₁₋₄ alkylene or R^(d)R^(c)N—C₁₋₄ alkylene;

n is 0, 1, 2 or 3;

each R² is independently F, C₂₋₆ alkynyl, OR^(b), C₃₋₁₂ carbocyclyl,C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-membered heterocyclyl, (3- to12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 14-membered heteroaryl, (5- to 14-memberedheteroaryl)-C₁₋₄ alkylene; or two adjacent R², together with the atomsto which they are attached, form a C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring or or 5- to10-membered heteroaromatic ring, and wherein each of the C₂₋₆ alkynyl,C₃₋₁₂ carbocyclyl, C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 14-membered heteroaryl, (5- to14-membered heteroaryl)-C₁₋₄ alkylene, C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring and 5- to 10-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F;

each R′ is independently F, Cl, Br, CN, NO₂, oxo (═O), OR^(b),—NR^(c)R^(d), R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 3- to6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄ alkylene,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-membered heteroaryl or (5-to 6-membered heteroaryl)-C₁₋₄ alkylene, and wherein each of the C₁₋₁₀alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,3- to 6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-memberedheteroaryl and (5- to 6-membered heteroaryl)-C₁₋₄ alkylene isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, Br, CN, NO₂, OR^(b),—NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆ haloalkyl, R^(b)O—C₁₋₄ alkylene orR^(d)R^(c)N—C₁₋₄ alkylene;

m is 1 or 2;

X has one of the following sub-formulae:

wherein R⁴ is H or C₁₋₆ alkyl, and wherein the C₁₋₆ alkyl is optionallysubstituted with one, two, three, or four U;

each R⁵, R⁶, R⁷ and R⁸ is independently H or C₁₋₆ alkyl; or R⁵ and R⁶,together with the carbon atom to which they are attached, form a C₃₋₈cycloalkyl group, 3- to 6-membered heterocyclic ring, C₆₋₁₀ aromaticring or 5- to 10-membered heteroaromatic ring; or R⁷ and R⁸, togetherwith the nitrogen atom to which they are attached, form a 3- to6-membered heterocyclic ring or 5- to 10-membered heteroaromatic ring,and wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 3- to 6-memberedheterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, or four U;

W is a C₃₋₁₂ carbocyclic ring or 3- to 12-membered heterocyclic ring;

each V and V′ is independently a C₃₋₁₂ cycloalkane ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring;

each R^(w) is independently F, Cl, Br, CN, NO₂, oxo (═O), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e), —S(═O)₂NR^(c)C(═O)R^(a),—S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂ alkylene, OR^(b), —NR^(c)R^(d),R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂ alkylene, C₁₋₆ alkyl, 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl, and wherein eachof the C₁₋₆ alkyl, 5- to 6-membered heteroaryl or 5- to 6-memberedheterocyclyl is independently unsubstituted or substituted with one,two, three, or four U;

each U is independently F, Cl, Br, NO₂, CN, oxo (═O), N₃, OR^(b),—NR^(c)R^(d), C₁₋₆ alkyl or C₁₋₆ haloalkyl;

each s and t is independently 0, 1, 2 or 3;

p is 1, 2 or 3; and

each R^(a), R^(b), R^(c), R^(d) and R^(e) is independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkylene, 3- to 6-membered heterocyclyl, (3- to6-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 10-membered heteroaryl, (5- to 10-memberedheteroaryl)-C₁₋₄ alkylene; or R^(c) and R^(d), together with thenitrogen atom to which they are attached, form a 3- to 6-memberedheterocyclic ring, and wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 3- to6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄ alkylene,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 10-membered heteroaryl, (5-to 10-membered heteroaryl)-C₁₋₄ alkylene and 3- to 6-memberedheterocyclic ring is independently unsubstituted or substituted withone, two, three, or four substituents independently selected from F, Cl,CN, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy or C₁₋₆ alkylamino.

In other embodiments, the invention relates to a compound having Formula(II), or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, X, R′, n and q are as defined herein.

In other embodiments, A is a C₃₋₁₂ carbocyclic ring, 3- to 12-memberedheterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring; and

q is 0, 1, 2, 3, 4 or 5.

In other embodiments, each R¹ and R³ is independently H, F, Cl,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), OR^(b), —NR^(c)R^(d), C₁₋₃alkyl, C₃₋₆ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to6-membered heteroaryl, and wherein each of the C₁₋₃ alkyl, C₃₋₆cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-memberedheteroaryl is independently unsubstituted or substituted with one, two,three or four substituents independently selected from F, Cl, OR^(b),—NR^(c)R^(d), C₁₋₃ alkyl, C₁₋₃ haloalkyl or R^(b)O—C₁₋₂ alkylene.

In other embodiments, each R² is independently F, C₂₋₆ alkynyl, OR^(b),C₃₋₆ carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene; or two adjacent R², together withthe atoms to which they are attached, form a C₅₋₆ carbocyclic ring, 5-to 6-membered heterocyclic ring, benzene ring or 5- to 6-memberedheteroaromatic ring, and wherein each of the C₂₋₆ alkynyl, C₃₋₆carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene, C₅₋₆ carbocyclic ring, 5- to6-membered heterocyclic ring, benzene ring and 5- to 6-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F.

In other embodiments, each R′ is independently F, Cl, Br, CN, NO₂,OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)NR^(c)R^(d), C₁₋₉ alkyl, C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene or 5- to 6-membered heteroaryl, and wherein each ofthe C₁₋₉ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 5- to 6-memberedheterocyclyl, phenyl, phenyl-C₁₋₄ alkylene and 5- to 6-memberedheteroaryl is independently unsubstituted or substituted with one, two,three, or four substituents independently selected from F, Cl, Br, CN,NO₂, OR^(b), —NR^(c)R^(d), methyl, ethyl, n-propyl or i-propyl.

In other embodiments, each R^(a), R^(b), R^(c), R^(d) and R^(e) isindependently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 3- to6-membered heterocyclyl, phenyl, phenyl-C₁₋₂ alkylene; or R^(c) andR^(d), together with the nitrogen atom to which they are attached, forma 5- to 6-membered heterocyclic ring, and wherein each of methyl, ethyl,i-propyl, n-propyl, n-butyl, t-butyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 3- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene and 5- to 6-membered heterocyclic ring isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, CN, OH, NH₂, C₁₋₃ alkyl,C₁₋₃ haloalkyl or methoxy.

In other embodiments, X has one of the following sub-formulae:

wherein W, V, V′, R⁵, R⁶, R⁷, R⁸, R^(w) and s are as defined herein.

In other embodiments, W is a C₆₋₈ carbocyclic ring or 6- to 8-memberedheterocyclic ring.

In other embodiments, V is a C₃₋₈ cycloalkane ring, 3- to 8-memberedheterocyclic ring, benzene ring or 5- to 6-membered heteroaromatic ring.

In other embodiments, V′ is a C₃₋₈ cycloalkane ring, 3- to 8-memberedheterocyclic ring, benzene ring or 5- to 6-membered heteroaromatic ring.

In other embodiments, each R^(w) is independently F, Cl, Br, CN, NO₂,oxo (═O), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e),—S(═O)₂NR^(c)C(═O)R^(a), —S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂alkylene, OR^(b), —NR^(c)R^(d), R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂alkylene, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolylor pyrazolyl, and wherein each of methyl, ethyl, i-propyl, n-propyl,n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted orsubstituted with one, two, three, or four U.

In other embodiments, each U is independently F, Cl, Br, CF₃, NO₂, CN,oxo (═O), N₃, OR^(b), —NR^(c)R^(d), methyl, ethyl, i-propyl, n-propyl,n-butyl or t-butyl.

In other embodiments, A is a C₅₋₆ carbocyclic ring, 5- to 6-memberedheterocyclic ring, benzene ring, naphthalene ring or 5- to 6-memberedheteroaromatic ring.

In other embodiments, each R² is independently F, ethynyl, propynyl,OR^(b), C₃₋₆ carbocyclyl, 5- to 6-membered heterocyclyl, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl, pyrrolyl, pyridyl,pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl,oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl,pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl,isoquinolyl, phenoxthinyl,

and wherein each ethynyl, propynyl, C₃₋₆ carbocyclyl, 5- to 6-memberedheterocyclyl, phenyl, naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl,benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl,quinolyl, isoquinolyl, phenoxthinyl,

is independently unsubstituted or substituted with one, two, three, fouror five R′, with the proviso that when m is 1, R² is not F.

In other embodiments, X has one of the following sub-formulae:

wherein R^(w), s and V′ are as defined herein

In other embodiments, A is a C₅₋₆ carbocyclic ring, 5- to 6-memberedheterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole,pyridine, pyrazole, imidazole, benzoimidazole, triazole, tetrazole,oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene, benzothiphene,pyrazine, pyridazine, pyrimidine, indole, purine, quinoline orisoquinoline.

In other embodiments, the invention relates to a compound having Formula(III) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(IV) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(V) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VI) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite,a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VII) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R¹, R², R³, m, n, s, V′ and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having Formula(VIII) or a stereoisomer, a tautomer, an N-oxide, a solvate, ametabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein A, R¹, R³, R′, n, q, s, V′ and R^(w) are as defined herein.

In other embodiments, the invention relates to a compound having one ofthe following structures, or a stereoisomer, a tautomer, an N-oxide, asolvate, a metabolite, a pharmaceutically acceptable salt or a prodrugthereof, but the compound is not limited to these structures:

In one aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein.

In certain embodiments, the pharmaceutical composition provided hereinfurther comprises a pharmaceutically acceptable carrier, adjuvant,vehicle or a combination thereof.

In certain embodiments, the pharmaceutical composition provided hereinfurther comprises one or more therapeutic agents.

In other embodiments, the therapeutic agent disclosed herein is ananti-influenza virus agent or anti-influenza virus vaccine.

In other embodiments, the pharmaceutical composition is in the form ofliquid, solid, semi-solid, gel or spray.

In other embodiments, the pharmaceutical composition, wherein thetherapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir,peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir,arbidol, ribavirin, stachyflin, ingavirin, fludase, CAS no.1422050-75-6, JNJ-872, AL-794, an influenza vaccine (FluMistQuadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax®or FluBlok®) or a combination thereof.

In another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for preventing, managing, treating or lessening a disorder ordisease caused by virus infection in a patient.

In certain embodiments, the virus infection disclosed herein isinfluenza virus infection.

In another aspect, provided herein is use of the compound or thepharmaceutical composition disclosed herein in the manufacture of amedicament for inhibiting RNA polymerase of the influenza virus.

In one embodiment, the salt is a pharmaceutically acceptable salt. Thephrase “pharmaceutically acceptable” refers to that the substance orcomposition must be chemically and/or toxicologically compatible withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

In another embodiment, the salts are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of the invention and/or for separatingenantiomers of compounds of the invention.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, subsalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds disclosed herein, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the presentinvention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.

Any formula given herein is also intended to represent isotopicallyunenriched forms as well as isotopically enriched forms of thecompounds. Isotopically enriched compounds have structures depicted bythe formulas given herein except that one or more atoms are replaced byan atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, and chlorine, such as ²H (deuterium, D), ³H, ¹¹C, ¹³C,¹⁴C, ¹⁸F, ³¹P, ³²P, ³⁶S, ³⁷Cl, ¹²⁵I, respectively.

In another aspect, the compounds of the invention include isotopicallyenriched compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically enriched compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F-enriched compound may be particularlydesirable for PET or SPECT studies. Isotopically-enriched compounds ofFormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent of a compound of Formula (I).The concentration of such a heavier isotope, specifically deuterium, maybe defined by the isotopic enrichment factor. The term “isotopicenrichment factor” as used herein means the ratio between the isotopicabundance and the natural abundance of a specified isotope. If asubstituent in a compound of this invention is denoted deuterium, suchcompound has an isotopic enrichment factor for each designated deuteriumatom of at least 3500 (52.5% deuterium incorporation at each designateddeuterium atom), at least 4000 (60% deuterium incorporation), at least4500 (67.5% deuterium incorporation), at least 5000 (75% deuteriumincorporation), at least 5500 (82.5% deuterium incorporation), at least6000 (90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation). Pharmaceutically acceptable solvates in accordance withthe invention include those wherein the solvent of crystallization maybe isotopically substituted, e.g., D₂O, d₆-acetone, DMSO-d₆.

Pharmaceutical Composition of the Compound of the Invention,Preparations and Administration

The invention provides a pharmaceutical composition containing atherapeutic effective amount of the compound of the invention or astereisomer thereof. In one embodiment, the pharmaceutical compositionfurther comprises at least one pharmaceutically acceptable carriers,diluents, adjuvants or excipients, and optionally other treating and/orpreventing ingredients. In one embodiment, the pharmaceuticalcomposition comprises an effective amount of at least onepharmaceutically acceptable carriers, diluents, adjuvants or excipients.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compound(s)described herein. The pharmaceutically acceptable carriers should bebiocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic anddevoid of other undesired reactions upon the administration to asubject. Standard pharmaceutical formulation techniques can be employed.

As described above, the pharmaceutically acceptable compositionsdisclosed herein further comprise a pharmaceutically acceptable carrier,an adjuvant, or a vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington: The Science andPractice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of PharmaceuticalTechnology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, MarcelDekker, New York, the contents of each of which is incorporated byreference herein, are disclosed various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumincompatible with the compounds disclosed herein, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other components of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methyl cellulose,hydroxypropyl methyl cellulose, wool fat, sugars such as lactose,glucose and sucrose; starches such as corn starch and potato starch;cellulose and its derivatives such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients such as cocoa butter and suppository waxes;oils such as peanut oil, cottonseed oil; safflower oil; sesame oil;olive oil; corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The pharmaceutically acceptable compositions can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, drops or patch), bucally, as an oral or nasal spray,or the like, depending on the severity of the infection being treated.

Liquid formulations for oral administration include, but not limited to,pharmaceutically acceptable emulsions, micro-emulsion, solution,suspension, syrup and elixir. In addition to the active ingredient, theliquid dosage forms may contain inert diluent commonly used in the art,such as, for example, water or other solvents, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor and sesame oils), glycerol,tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters ofsorbitan, and mixtures thereof. Addition to inert diluents, the oralcompositions can also contain adjuvants such as wetting agents,emulsifiers or suspending agent, sweeteners, flavorings and fragrances.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound or a composition describedherein, it is often desirable to slow the absorption of the compoundfrom subcutaneous or intramuscular injection. This may be accomplishedby the use of a liquid suspension of crystalline or amorphous materialhaving poor water solubility. The rate of absorption of the drug thendepends upon its rate of dissolution which, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolic acid. Depending upon the ratioof compound to polymer and the nature of the particular polymeremployed, the rate of compound release can be controlled. Examples ofother biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are specificallysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

The solid dosage forms for oral administration include capsules,tablets, pills, powders and granules. In such solid dosage forms, theactive compounds are mixed with at least one pharmaceutically acceptableinert excipients or carrier, such as sodium citrate or calcium phosphateand/or (a) fillers or swelling agents such as starch, lactose, sucrose,glucose, mannitol and silicic acid; (b) adhesives such ascarboxymethylcellulose, alginates, gelatin, polyethylene pyrrole ketone,sucrose and gum arabic; (c) moisturizing agents such as glycerol; (d)disintegrating agents such as agar, calcium carbonate, potato starch ortapioca starch, alginic acid, certain silicates and sodium carbonate;(e) blocker solution, such as paraffin; (f) absorption promoter such asquaternary ammonium compounds; (g) wetting agents such as cetyl alcoholand glycerol monostearate; (h) absorbents such as kaolin and bentonite,(i) lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycol, laurylsodium sulfate, and mixtures thereof. In thecase of capsules, tablets and pills, the pharmaceutical compositions mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings and other coatings well known in thepharmaceutical formulating art. In such solid dosage forms, the activecompound may be admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms may also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions that can be used include polymericsubstances and waxes.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Specifically, the compositions areadministered orally, intraperitoneally or intravenously. Specifically,the compositions are administered orally, intraperitoneally orintravenously.

Sterile injectable forms of the compositions described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilcan be employed including synthetic mono- or diglycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions described herein may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,specifically, as solutions in isotonic, pH adjusted sterile saline,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The compounds for use in the methods of the invention can be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for subjects undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form can be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form can be the same or different foreach dose.

Uses of the Compounds and Pharmaceutical Compositions

The compounds and pharmaceutical compositions provided herein can beused in the manufacture of medicaments for preventing, treating orlessening a disorder or disease caused by virus infection in a patient.In some embodiment, the virus infection is influenza virus infection.

Also provided herein are the uses of the compounds and pharmaceuticalcompositions described above in the manufacture of medicaments which areinhibitors of influenza virus RNA polymerase.

Provided herein is a method of treating, preventing or delaying theinfections caused by viruses, and wherein the method comprisesadministering to the patent a therapeutically effective amount of thecompound or the pharmaceutical composition described herein to a patientin need of treatment. Wherein the virus is an influenza virus. And, thecompounds or pharmaceutical compositions thereof can be co-administeredwith other therapies or therapeutic agents. The co-administration can beperformed simultaneously, sequentially, or in a certain time interval.

Doses of the compound or pharmaceutical composition needed forimplementing functions such as treating, preventing or delaying usuallydepend on the particular compound to be administered, patient, specificdisease or disorder and severity thereof, route and frequency ofadministration and so on, and need to be determined by the attendingdoctor in accordance with specific conditions. For example, when thecompound or pharmaceutical composition of the present invention isadministrated intravenously, the administration may be once a week oreven longer intervals.

As described above, the present invention provides a novel class ofcompounds, and wherein the compounds can be used as inhibitors of theinfluenza virus RNA polymerase. The compounds of the invention aresuitable for preparing medicaments as various dosage forms, which can beused for treating seasonal flu, avian flu, swine flu as well astamiflu-resistant influenza virus mutants.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of animals such as companion animals,exotic animals and farm animals. In other embodiments, the animalsdisclosed herein include horses, dogs, and cats. As used herein, thecompounds disclosed herein include the pharmaceutically acceptablederivatives thereof.

General Synthetic Procedures

For the purpose of describing the invention, the following examples arelisted. It should be understood that, the invention is not limited tothese examples, and the present invention only provide the method topractice the invention.

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(I), except where further noted. The following non-limiting schemes andexamples are presented to further exemplify the invention.

Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of other compoundsdisclosed herein, and alternative methods for preparing the compoundsdisclosed herein are deemed to be within the scope disclosed herein. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company, Alfa Chemical Company and J&K Scientific Ltd. and wereused without further purification unless otherwise indicated. Commonsolvents were purchased from commercial suppliers such as Shantou XiLongChemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd.,Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd.,Tianjing Fuchen Chemical Reagent Factory, Wuhan XinHuayuan technologydevelopment co., LTD., Qingdao Tenglong Reagent Chemical Ltd., QingdaoOcean Chemical Factory, Beijin Ouhe Technology Co., Ltd., ShanghaiTopbiochem Technology Co., Ltd, and Accela ChemBio Co., Ltd.

Anhydrous THF, 1,4-dioxane, toluene, and ether were obtained byrefluxing the solvent with sodium. Anhydrous CH₂Cl₂ and CHCl₃ wereobtained by refluxing the solvent with calcium hydride. EtOAc, PE,n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were treatedwith anhydrous Na₂SO₄ prior use.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silicagel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

¹H NMR spectra were recorded at rt with a Bruker 400 MHz or 600 MHzspectrometer using CDCl₃, d₆-DMSO, CD₆OD or d₆-acetone as solvent(reported in ppm), and using TMS (0 ppm) or chloroform (7.26 ppm) as thereference standard. When peak multiplicities were reported, thefollowing abbreviations were used: s (singlet), d (doublet), t(triplet), m (multiplet), br (broadened), dd (doublet of doublets), anddt (doublet of triplets). Coupling constants, when given, are reportedin Hertz (Hz).

Low-resolution mass spectral (MS) data were determined on an Agilent6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent ZorbaxSB-C18 column (2.1×30 mm, 3.5 μm). The flow rate was 0.6 mL/min; themobile phases consisted of a combination of A (0.1% formic acid inCH₃CN) and B (0.1% formic acid in H₂O) in gradient mode (5% to 95%), andan ESI source was used, the peak of HPLC was recorded with UV-Visdetection at 210/254 nm.

Purification of compound by preparative chromatography was implementedon Agilent 1260 Series high performance liquid chromatography (Pre-HPLC)or Calesep Pump 250 Series high performance liquid chromatography(Pre-HPLC) with UV detection at 210/254 nm (column: NOVASEP, 50/80 mm.DAC).

The following abbreviations are used throughout the specification:

AcOH, HAc, HOAc, CH₃COOH acetic acidAcOK, KOAc, CH₃COOK potassium acetateBnOH phenylcarbinolBu₄NF tetrabutylammonium fluorideBOC, Boc tert-butoxycarbonyl(Boc)₂O di-tert-butyl dicarbonaten-BuOH n-butyl alcoholCHCl₃ chloroformCDCl₃ chloroform-dCD₃OD methyl alcohol-d₄DCM, CH₂Cl₂ dichloromethaneCH₃CN, MeCN acetonitrileCH₃Cl chloromethaneCH₃I iodomethaneCH₃SO₂Cl, MsCl methylsulfonyl chlorideCbz benzyloxycarbonylCL clearanceDIEA, DIPEA, iPr₂Net N,N-diisopropylethylamineDMF N,N-dimethylformamide, dimethylformamideDMF-DMA N,N-dimethylformamide dimethyl acetalDME dimethyl etherDMAP 4-dimethylaminopyridineDMSO dimethylsulfoxideDMSO-d₆ dimethyl sulfoxide-d₆, deuterated DMSODPPA diphenylphosphoryl azideEA, EtOAc ethyl acetateEt₃N, TEA triethylamineEt₂O diethyl etherEtOH ethyl alcoholEC₅₀ 50% effective concentrationg gramwt weight fractionh hour, hoursH₂ hydrogenH₂O waterHCl hydrogen chlorideH₂O₂ hydrogen peroxideH₃PO₄ phosphoric acidH₂SO₄ sulfuric acidHNO₃ nitric acidHCOOK potassium formateHCOONH₄ ammonium formateHPLC high performance liquid chromatographyHPTLC high performance thin layer chromatographyHRMS high resolution mass spectrumI₂ iodineFe ironMgSO₄ magnesium sulfateCH₃OH, MeOH methanolMeI, CH₃I iodomethanemL, ml millilitermin minute, minutesN₂ nitrogenNH₃ ammonia

NMP N-methylprrolidone

NaHCO₃ sodium bicarbonateNaBH₄ sodium borohydrideNaBH₃CN sodium cyanoborohydrideNaOMe, NaOCH₃, CH₃ONa sodium methoxideNaOH sodium hydroxideNaCl sodium chlorideNaH₂PO₄ sodium dihydrogen phosphateNaH sodium hydrideNaI sodium iodideNa₂SO₄ sodium sulfateNa₂S₂O₃ sodium thiosulfate

NBS N-bromosuccinimide NIS N-iodosuccinimide NCS N-chlorosuccinimide

NH₄Cl ammonium chlorideNH₂OH.HCl hydroxylamine hydrochloridepsi pound per square inchPd/C palladium on activated carbonPd(OAc)₂ palladium diacetatePd(OH)₂ palladium hydroxidePd(PPh₃)₄ tetrakis(triphenylphosphine)palladiumPd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium(II) chloridePd(dppf)Cl₂, PdCl₂(dppf)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl₂.CH₂Cl₂1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complexPd(dtbpf)Cl₂[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladiumP(t-Bu)₃ tri-tert-butylphosphinePE petroleum ether (60-90° C.)POCl₃ phosphorus oxychlorideK₂CO₃ potassium carbonateK₃PO₄ potassium phosphateKOH potassium hydroxideRT, rt, r.t. room temperatureRt retention timeSOCl₂ thionyl chlorideSI therapeutic indext-BuOK potassium tert-butoxideTHF tetrahydrofuranTFA trifluoroacetic acidTBAI tetrabutylammonium iodideTBS tris(hydroxymethyl)aminomethane saline bufferTsCl tosyl chloride

Ts Tosyl

Vss apparent volume of distributionX-Phos 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenylZn zincμL microliter

The following schemes list the synthetic steps of the compounds of theinvention, and wherein R¹, R², R³, R^(w), R′, n, q, s, V′ and A are asdefined herein, R^(h) is H or F, and R^(g) is OH or Cl.

The intermediate having Formula (6) can be prepared by the processillustrated in scheme 1. Firstly, compound (1) can react with abromination reagent (eg., bromine, NBS, etc.) at rt in a polar solvent(eg., N,N-dimethylformamide) or medium polar solvent (eg.,dichloromethane) to give compound (2). Compound (2) can react withp-tosyl chloride (3) to give compound (4). Compound (4) can react withcompound (5) in the presence of a palladium catalyst (eg., Pd(dppf)Cl₂,Pd(PPh₃)₄, etc.,) to give intermediate (6).

Compound having Formula (17) can be prepared by the process illustratedin scheme 2. Firstly, compound (7) can react with compound (8) in theabsence of light to give compound (9). Compound (9) can undergo aring-opening reaction in the presence of a base (such as sodiummethoxide, and the like) to give compound (10). Then, compound (10) canreact with DPPA and phenylcarbinol (11) undergoing a rearrangementreaction under an alkaline condition to give compound (12). The aminoprotecting group on compound (12) can be removed under a reductioncondition to give compound (13). Coupling reaction between compound (13)and compound (14) can happen under an alkaline condition to givecompound (15). Suzuki cross-coupling reaction can occur between compound(15) and compound (6) in the presence of a palladium catalyst to givecompound (16). At last, protecting groups on compound (16) can beremoved in the presence of a base to give compound (17).

Compound having Formula (24) can be prepared by the process illustratedin scheme 3. Firstly, compound (18) can react with urea (19) under aheating condition to give compound (20). Compound (20) can undergo achlorination reaction in the presence of phosphorus oxychloride to givecompound (21). Then compound (21) can react with compound (13) under analkaline condition to give compound (22). Suzuki cross-coupling reactioncan occur between compound (22) and compound (6) in the presence of apalladium catalyst to give compound (23). At last, protecting groups oncompound (23) can be removed in the presence of a base to give compound(24).

Compound having Formula (30) can be prepared by the process illustratedin scheme 4. Firstly, Suzuki cross-coupling reaction can occur betweencompound (25) and boric acid compound (26) to give compound (27). Thencompound (27) can react with compound (13) under an alkaline conditionto give compound (28). And Suzuki cross-coupling reaction can occurbetween compound (28) and compound (6) in the presence of a palladiumcatalyst to give compound (29). At last, protecting groups on compound(29) can be removed in the presence of a base to give compound (30).

Compound having Formula (36) can be prepared by the process illustratedin scheme 5. Firstly, compound (31) can react with compound (13) underan alkaline condition to give compound (32). Then compound (32) andboric acid compound (33) can undergo Suzuki cross-coupling reaction togive compound (34). And Suzuki cross-coupling reaction can occur betweencompound (34) and compound (6) in the presence of a palladium catalystto give compound (35). At last, protecting groups on compound (35) canbe removed in the presence of a base to give compound (36).

Compound having Formula (43) can be prepared by the process illustratedin scheme 6. Firstly, compound (E) can react with compound (38) to givecompound (39). Then compound (39) and compound (40) can undergo acondensation reaction to give compound (41). And Suzuki cross-couplingreaction can occur between compound (41) and compound (6) in thepresence of a palladium catalyst to give compound (42). At last,protecting groups on compound (42) can be removed in the presence of abase to give compound (43).

Compound having Formula (53) can be prepared by the process illustratedin scheme 7. Firstly, compound (44) can react with DPPA and compound(11) under an alkaline condition to give compound (45). Then compound(45) can undergo a reduction reaction under a certain condition (such asin the presence of Pd/C catalyst and in a hydrogen atmosphere) to givecompound (46). Compound (46) can react with compound (47) under analkaline condition to give compound (48). Then an amino protection groupon compound (48) can be removed under an acid condition to give compound(49). Compound (49) and compound (50) can undergo a condensationreaction to give compound (51). And Suzuki cross-coupling reaction canoccur between compound (51) and compound (6) in the presence of apalladium catalyst to give compound (52). At last, a protecting group oncompound (52) can be removed under an alkaline condition to givecompound (53).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples are used for illustrating the invention, but cannot be construed to limit the scope of the invention.

EXAMPLES OF PREPARATION

Using parts of the compounds of the invention as examples, thepreparations of the compounds of the present invention have beendescribed in detail in the following examples.

Example 1:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: meso-endo-tetrahydro-4,7-ethanoisobenzofuran-1,3-dione

To a 2000 mL dried flask were added maleic anhydride (100 g, 1.02 mol)and chloroform (1000.0 mL) in turn, then the mixture was cooled to 0°C., and 1,3-cyclohexadiene (112.5 mL, 1.12 mol) was added dropwise.After the addition, the mixture was warmed to rt, and stirred overnightin the absence of light. After the reaction was completed, the mixturewas concentrated in vacuo to remove the solvent. To the residue wasadded methanol (700.0 mL), and the resulting mixture was heated to 50°C. and stirred for 10 min, then cooled to 0° C. and stirred for 30 min.The mixture was filtered, and the filter cake was dried in vacuo at 45°C. to give the title compound as a white solid (147 g, 81%).

MS (ESI, pos. ion) m/z: 179.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 6.28 (dd, J=4.2, 3.4 Hz, 2H), 3.29(s, 2H), 3.04 (s, 2H), 1.61 (d, J=7.9 Hz, 2H), 1.22 (d, J=7.6 Hz, 2H).

Step 2:(+/−)-trans-3-(methoxycarbonyl)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid

To a dried flask was addedmeso-endo-tetrahydro-4,7-ethanoisobenzofuran-1,3-dione (33.50 g, 188.01mmol), then a solution of sodium methoxide in methanol (5 M, 300.8 mL)was added dropwise at 0° C. After the addition, the mixture was warmedto rt and stirred for 4 days, then concentrated in vacuo to remove partof the methanol (about 120 mL). The residue was added slowly into 0° C.aqueous hydrochloric acid solution (277 mL, 18% wt), and there was awhite solid precipitated out. The mixture was concentrated in vacuo toremove methanol, and the residue was stirred at 0° C. for 30 min, thenfiltered by suction. The filter cake was washed with water three timesand dried in vacuo to give the title compound as a white solid (37.19 g,94%).

MS (ESI, neg. ion) m/z: 209.0 [M−H]⁻;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 6.34 (s, 1H), 6.17 (s,1H), 3.65 (s, 3H), 2.94 (s, 1H), 2.91 (d, J=4.4 Hz, 1H), 2.86 (d, J=2.4Hz, 1H), 2.72 (s, 1H), 1.48-1.58 (m, 1H), 1.34-1.44 (m, 1H), 1.26-1.16(m, 1H), 1.09-0.99 (m, 1H).

Step 3: methyl(+/−)-trans-3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-5-ene-2-carboxylate

A solution of(+/−)-trans-3-(methoxycarbonyl)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid(6.0 g, 29 mmol) in toluene (50 mL) was degassed and filled withnitrogen for three times, then diphenyl azidophosphate (7.0 mL, 32 mmol)and triethylamine (4.0 mL, 29 mmol) were added in turn by syringe. Themixture was heated to 90° C. and stirred for 2 hours, thenphenylcarbinol (3.0 mL, 29 mmol) was added dropwise by syringe. Themixture was stirred for further 3 days maintaining at this temperature.The reaction mixture was cooled to rt, and ethyl acetate (60 mL) wasadded to dilute the mixture. The resulting mixture was washed withsaturated aqueous sodium bicarbonate (60 mL×2) and saturated brine (50mL) in turn, and the organic layer was dried over anhydrous sodiumsulfate, filtered, then the filtrate concentrated in vacuo. The residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) togive the title compound as a yellow oil (8.25 g, 92%).

MS (ESI, pos. ion) m/z: 316.1 [M+H]⁺.

Step 4: methyl (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate

To an autoclave were added (+/−)-trans-methyl3-(((benzyloxy)carbonyl)amino) bicyclo[2.2.2]oct-5-ene-2-carboxylate(8.21 g, 26.0 mmol), tetrahydrofuran (20 mL) and methanol (20 mL) inturn. To the solution was added Pd/C (10% wt of Pd, 1.40 g), and themixture was stirred at rt overnight under a hydrogen pressure of 2.76bar. The reaction mixture was filtered through a celite pad to removethe catalyst, then the filter cake was washed with methanol (20 mL) andethyl acetate (20 mL) in turn. The combined filtrates were concentratedin vacuo to give colourless oil, which was purified by silica-gel columnchromatography (DCM/MeOH (v/v)=20/1-10/1) to give the title compound ascolourless oil (3.95 g, 83%).

MS (ESI, pos. ion) m/z: 184.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.68 (s, 3H), 3.31 (d, J=6.7 Hz, 1H),2.11 (d, J=6.7 Hz, 1H), 1.98-1.91 (m, 1H), 1.83-1.71 (m, 1H), 1.60-1.33(m, 10H).

Step 5: (+/−)-trans-methyl3-((2-chloroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (20 mL) were added (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (1.83 g, 9.99 mmol),2,4-dichloroquinazoline (2.5 g, 15 mmol) and DIPEA (8.7 mL, 50 mmol).The mixture was stirred at rt overnight. The reaction mixture wasquenched with water (100 mL). The resulting mixture was extracted withethyl acetate (50 mL×2). The combined organic layers were washed withsaturated brine (80 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) togive the title compound as a white solid (3.13 g, 95%).

MS (ESI, pos. ion) m/z: 356.8 [M+H]⁺.

Step 6: 3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine

To the solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1 g, 7.34 mmol)in DMF (10 mL) was added bromine (0.75 mL, 14.5 mmol). The mixture wasstirred at rt for 4 hours. The reaction mixture was quenched withsaturated aqueous sodium thiosulfate (100 mL). The resulting mixture wasextracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with saturated brine (100 mL×3), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as yellow powder (0.6 g, 40%).

MS (ESI, pos. ion) m/z: 216.9 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.23 (s, 1H), 8.35-8.21 (m, 1H),7.81 (d, J=2.7 Hz, 1H), 7.71 (dd, J=8.9, 2.6 Hz, 1H).

Step 7: 3-bromo-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.74 g, 2.0mmol) in THF (5 mL) was added NaH (127 mg, 3.0 mmol) at 0° C., and themixture was stirred for 30 min maintaining at this temperature, thenTsCl (458 mg, 2.4 mmol) was added. The resulting mixture was warmed tort and stirred overnight. The reaction mixture was quenched with water(50 mL), and the resulting mixture was partitioned. The aqueous layerwas extracted with ethyl acetate (50 mL×2). The combined organic layerswere washed with saturated brine (80 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a yellow solid (740 mg, 90%).

MS (ESI, pos. ion) m/z: 370.8 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.32 (s, 1H), 8.06 (d, J=8.3 Hz, 2H),7.84 (s, 1H), 7.47 (dd, J=7.8, 2.6 Hz, 1H), 7.29 (d, J=8.3 Hz, 2H), 2.38(s, 3H).

Step 8:5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To DME (5 mL) were added3-bromo-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg, 0.22 mmol),Pd(dppf)Cl₂ (70 mg, 0.09 mmol) and KOAc (144 mg, 0.47 mmol). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then tothe mixture was added bis(pinacolato)diboron (190 mg, 0.71 mmol). Themixture in a tube was sealed and stirred at 105° C. for 2 h undermicrowave condition. After the reaction was completed, the reactionmixture was diluted with ethyl acetate (20 mL). Then the mixture wasfiltered through a celite pad, and the filter cake was washed with ethylacetate (20 mL×2). The combined filtrates were concentrated in vacuo,and the residue was purified by silica-gel column chromatography(PE/EtOAc (v/v)=4/1) to give the title compound as a yellow solid (130mg, 65.9%).

MS (ESI, pos. ion) m/z: 417.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.27 (d, J=1.2 Hz, 1H), 8.19 (s, 1H),8.08 (d, J=8.3 Hz, 2H), 7.89 (dd, J=8.5, 2.7 Hz, 1H), 7.30 (s, 1H), 7.28(s, 1H), 2.39 (s, 3H), 1.37 (s, 12H).

Step 9: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixed solvent of 2-methyltetrahydrofuran (8 mL) and water (1 mL)were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(305 mg, 0.73 mmol), K₃PO₄ (276 mg, 1.31 mmol), Pd₂(dba)₃ (46 mg, 0.1mmol), methyl3-((2-chloroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(150 mg, 0.43 mmol) and X-phos (23 mg, 0.1 mmol). The air in the mixturewas removed by bubbling with nitrogen for 10 min. The mixture in asealed tube was stirred at 110° C. for 3 hours. The mixture was dilutedwith ethyl acetate (20 mL) and then filtered through a celite pad. Thefiltrate was partitioned and the organic layer was concentrated invacuo, then the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (255mg, 97%).

MS (ESI, pos. ion) m/z: 600.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.86 (dd, J=9.0, 2.8 Hz, 1H), 8.78 (s,1H), 8.33 (d, J=1.9 Hz, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.2 Hz,1H), 7.73 (dd, J=15.8, 7.6 Hz, 2H), 7.44 (t, J=7.2 Hz, 1H), 7.29 (d,J=8.9 Hz, 3H), 5.87 (d, J=6.3 Hz, 1H), 4.98 (s, 1H), 3.76 (s, 3H), 2.39(s, 3H), 2.16-2.08 (m, 2H), 1.81-1.69 (m, 6H), 1.29-1.24 (m, 2H).

Step 10:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(150 mg, 0.25 mmol) in THF/MeOH (v/v=1/1, 8 mL) was added aqueous sodiumhydroxide solution (4 M, 0.2 mL, 0.8 mmol). The mixture was stirred at30° C. overnight, then diluted with water (10 mL). The resulting mixturewas acidified with hydrochloric acid (1 M) to pH about 6.0, thenextracted with ethyl acetate (15 mL×3). The combined organic layers werewashed with saturated brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated in vacuo to remove thesolvent. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (80mg, 74%).

MS (ESI, pos. ion) m/z: 432.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 432.1831 [M+H]⁺, (C₂₄H₂₃FN₅O₂)[M+H]⁺theoretical value: 432.1836;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 13.18 (s, 1H), 9.49 (s, 1H), 8.92 (s,1H), 8.63 (d, J=7.9 Hz, 1H), 8.57 (d, J=8.4 Hz, 1H), 8.43 (s, 1H), 8.00(s, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 5.19 (s, 1H), 3.16 (s, 1H), 2.14(s, 1H), 2.06 (s, 1H), 1.85 (s, 3H), 1.57 (m, 6H).

Example 2:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (15 mL) were added (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (0.68 g, 3.69 mmol),2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.13 g, 2.46 mmol) and DIPEA(4.5 mL, 24.6 mmol). The mixture was stirred at 65° C. overnight. Thereaction mixture was quenched with water (100 mL). The resulting mixturewas extracted with ethyl acetate (50 mL×2). The combined organic layerswere washed with saturated brine (80 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a white solid (862 mg, 17%).

MS (ESI, pos. ion) m/z: 350.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.75 (d, J=5.1 Hz, 1H), 4.43 (t, J=5.3Hz, 1H), 3.77 (s, 3H), 2.68 (t, J=5.9 Hz, 2H), 2.35 (d, J=5.7 Hz, 1H),2.29-2.23 (m, 2H), 2.05 (s, 1H), 1.96 (d, J=2.5 Hz, 1H), 1.89-1.76 (m,6H), 1.67-1.54 (m, 5H), 1.26 (d, J=7.1 Hz, 1H).

Step 2: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixed solvent of 2-methyltetrahydrofuran (8 mL) and water (1 mL)were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(251 mg, 0.59 mmol), K₃PO₄ (253 mg, 1.18 mmol), Pd₂(dba)₃ (83 mg, 0.1mmol), (+/−)-trans-methyl3-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(150 mg, 0.43 mmol) and X-phos (43 mg, 0.1 mmol). The air in the mixturewas removed by bubbling with nitrogen for 10 min. The mixture in asealed tube was stirred at 110° C. for 3 hours. The mixture was dilutedwith ethyl acetate (20 mL), and the resulting mixture was filteredthrough a celite pad. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a white solid (245 mg, 98%).

MS (ESI, pos. ion) m/z: 605.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66 (dd, J=9.0, 2.8 Hz, 1H), 8.61 (s,1H), 8.12 (d, J=8.4 Hz, 2H), 7.28 (s, 3H), 3.71 (s, 3H), 2.78 (t, J=5.6Hz, 2H), 2.39 (d, J=3.2 Hz, 4H), 2.06 (s, 1H), 2.01 (s, 1H), 1.89 (d,J=5.6 Hz, 5H), 1.76-1.67 (m, 5H), 1.37 (s, 3H), 1.27 (d, J=6.0 Hz, 3H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl) amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(295 mg, 0.49 mmol) in acetonitrile (3 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 0.3 mL, 1.2 mmol). The mixturewas stirred at 65° C. for 6.5 hours, and then diluted with water (10mL). The resulting mixture was extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with saturated brine (30 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound as a white solid (143 mg, 65%).

MS (ESI, pos. ion) m/z: 450.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.58 (s, 1H), 8.70 (dd, J=9.4, 2.6 Hz,1H), 8.36 (s, 1H), 8.23 (s, 1H), 4.81 (t, J=5.7 Hz, 1H), 4.66 (d, J=6.6Hz, 1H), 3.64 (s, 3H), 2.81 (d, J=5.6 Hz, 2H), 2.41 (d, J=5.7 Hz, 1H),2.35 (d, J=6.0 Hz, 2H), 2.05 (s, 2H), 1.88 (d, J=5.2 Hz, 5H), 1.73-1.49(m, 7H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(105 mg, 0.27 mmol) in THF/MeOH (v/v=1/1, 8 mL) was added aqueous sodiumhydroxide solution (4 M, 0.6 mL, 2.4 mmol). The mixture was stirred at30° C. overnight, then diluted with water (10 mL). The resulting mixturewas acidified with hydrochloric acid (1 M) to pH about 6.0, thenextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with saturated brine, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated in vacuo to remove thesolvent. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (105mg, 88%).

MS (ESI, pos. ion) m/z: 436.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 436.2143 [M+H]⁺, (C₂₄H₂₆FN₅O₂)[M+H]⁺theoretical value: 436.2149;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.35 (s, 1H), 8.57 (dd, J=9.7, 2.6Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 6.68 (s, 1H), 4.78 (s, 1H), 2.97(d, J=6.4 Hz, 1H), 2.68 (s, 2H), 2.51 (s, 3H), 2.41 (s, 1H), 2.00 (s,1H), 1.92 (s, 1H), 1.77 (s, 6H), 1.33 (d, J=7.2 Hz, 2H), 1.21 (s, 2H).

Example 3:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(4-methoxyphenyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (5.5 mL, 48 mmol) in THF (70mL) were added palladium acetate (0.147 g, 0.64 mmol),triphenylphosphine (0.353 g, 1.28 mmol), 4-methoxybenzeneboronic acid (5g, 31.9 mmol) and aqueous sodium carbonate solution (1 M, 64 mL, 64mmol). The mixture was stirred at 60° C. for 6 h. After the reaction wascompleted, the mixture was cooled to rt, and concentrated in vacuo toremove the solvent. To the residue was added H₂O (100 mL), and themixture was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with saturated brine (100 mL), dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography (PE)to give the title compound as a white solid (5.58 g, 68%).

MS (ESI, pos. ion) m/z: 255.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.07 (dd, J=9.4, 2.4 Hz, 2H), 7.60 (s,1H), 7.08-6.99 (m, 2H), 3.91 (s, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of 2,4-dichloro-6-(4-methoxyphenyl)pyrimidine (1 g, 3.92mmol) and (+/−)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate(1 g, 5.88 mmol) in N,N-dimethylformamide (20 mL) was added potassiumcarbonate (0.813 g, 5.88 mmol). The mixture was stirred at 50° C.overnight. After the reaction was completed, the mixture was dilutedwith H₂O (70 mL), and the resulting mixture was extracted with ethylacetate (100 mL×3). The combined organic layers were washed withsaturated brine (100 mL), dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated in vacuo to remove the solvent. Theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=20/1-5/1) to give the title compound as a white solid (1.01 g,64%).

MS (ESI, pos. ion) m/z: 402.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.98 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.9Hz, 2H), 6.72 (s, 1H), 5.46 (d, J=6.3 Hz, 1H), 4.32 (s, 1H), 3.88 (s,4H), 3.74 (s, 3H), 2.39 (d, J=5.1 Hz, 1H), 2.08 (s, 1H), 1.90-1.84 (m,1H), 1.78-1.71 (m, 2H), 1.70-1.63 (m, 4H), 1.58 (d, J=10.2 Hz, 2H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added (+/−)-trans-methyl3-((2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (550 mg, 1.368mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(630 mg, 1.513 mmol), potassium carbonate (380 mg, 2.75 mmol),Pd(dppf)Cl₂ (120 mg, 0.147 mmol), 1,4-dioxane (15 mL) and H₂O (0.5 mL).The air in the mixture was removed by bubbling with nitrogen for 10 min.The mixture in microwave tube was stirred at 110° C. undergoing amicrowave reaction for 2 h. The mixture was filtered through a celitepad, and the filter cake was washed with ethyl acetate. The combinedfiltrates was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (n-hexane/EtOAc (v/v)=15/1) to give thetitle compound as a yellow solid (816 mg, 91%).

MS (ESI, pos. ion) m/z: 656.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.70 (s, 1H), 8.32 (d, J=1.8 Hz, 1H),8.13 (s, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.29 (s, 1H),7.28 (s, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 6.68 (s, 1H), 5.25 (s, 1H),3.91 (s, 3H), 3.73 (s, 3H), 2.45 (d, J=5.3 Hz, 1H), 2.38 (s, 3H), 1.98(s, 1H), 1.84 (d, J=11.8 Hz, 2H), 1.75-1.65 (m, 6H), 1.62-1.53 (m, 2H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(816 mg, 1.244 mmol) in 1,4-dioxane (10 mL) was added a solution ofhydrogen chloride in dioxane (4 M, 10 mL, 40 mmol). The mixture wasstirred at 65° C. overnight. After the reaction was completed, themixture was diluted with ethyl acetate (20 mL), and the resultingmixture was washed with saturated aqueous sodium bicarbonate (20 mL).The organic layer was dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (n-hexane/EtOAc (v/v)=5/1) to give thetitle compound as a brown solid (350 mg, 56%).

MS (ESI, pos. ion) m/z: 502.2 [M+H]⁺.

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(350 mg, 0.69 mmol) in a mixed solvent of MeOH (5 mL), THF (5 mL) andH₂O (5 mL) was added sodium hydroxide (280 mg, 7.00 mmol). The mixturewas stirred at rt overnight. After the reaction was completed, themixture was diluted with 2-methyl tetrahydrofuran (20 mL), and themixture was was adjusted with diluted hydrochloric acid (1 M) to pH 6.0.The resulting mixture was extracted with 2-methyl tetrahydrofuran (20mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=1/1) to give the title compound as a light yellow solid (270 mg,79%).

MS (ESI, pos. ion) m/z: 476.4 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.78 (dd, J=9.5, 2.5 Hz, 1H), 8.40 (s,1H), 8.17 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.09 (s, 1H), 7.07 (s,1H), 6.68 (s, 1H), 3.89 (s, 3H), 2.56 (d, J=5.9 Hz, 1H), 2.09 (s, 1H),2.03 (s, 1H), 1.91 (d, J=11.4 Hz, 2H), 1.80-1.70 (m, 4H), 1.57 (s, 1H),1.54 (s, 1H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.05, 163.07, 162.34, 161.21,156.85, 155.26, 146.46, 131.73, 131.53, 130.62, 128.21, 119.09, 119.03,115.16, 114.56, 114.33, 60.24, 55.72, 28.80, 28.57, 26.02, 24.17, 21.38,19.42, 14.53.

Example 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-6-phenylpyrimidine

To a solution of 2,4,6-trichloropyrimidine (0.29 mL, 2.5 mmol) in THF (5mL) were added palladium acetate (8 mg, 0.035 mmol), triphenylphosphine(18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6 mmol) and aqueoussodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). The mixture wasstirred at 60° C. for 6 h under nitrogen protection. After the reactionwas completed, the mixture was cooled to rt, and concentrated in vacuoto remove the organic solvent. To the residue was added H₂O (10 mL), andthe resulting mixture was extracted with ethyl acetate (10 mL×3). Thecombined organic layers were washed with saturated brine (10 mL), driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE) to give the title compound as a white solid (0.225g, 61%).

MS (ESI, pos. ion) m/z: 225.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H),7.63-7.50 (m, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of 2,4-dichloro-6-phenylpyrimidine (1.52 g, 6.7 mmol) and(±)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (1.84 g, 10.0mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate(0.92 g, 6.7 mmol). The mixture was stirred at rt overnight. After thereaction was completed, the mixture was diluted with H₂O (50 mL), andthe resulting mixture mixture was extracted with ethyl acetate (40mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered, and the filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=20/1-10/1) to give the titlecompound as a white solid (1.65 g, 66%).

MS (ESI, pos. ion) m/z: 372.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.04-7.91 (m, 2H), 7.51-7.41 (m, 3H),6.78 (s, 1H), 5.41 (s, 1H), 4.32 (s, 1H), 3.73 (s, 3H), 2.38 (d, J=5.1Hz, 1H), 2.07 (s, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.70-1.60 (m, 4H),1.57 (m, 2H), 1.51-1.41 (m, 1H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(240 mg, 0.57 mmol), (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(220 mg, 0.59 mmol), potassium carbonate (160 mg, 1.16 mmol),Pd(dppf)Cl₂ (43 mg, 0.06 mmol), 1,4-dioxane (4 mL) and H₂O (0.5 mL). Theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture in microwave tube was stirred at 110° C. undergoing a microwavereaction for 1 h. The mixture was filtered through a celite pad, and thefilter cake was washed with ethyl acetate (30 mL). The combinedfiltrates were concentrated in vacuo, and the residue was purified bysilica gel column chromatography (n-hexane/EtOAc (v/v)=10/1) to give thetitle compound as a white solid (218 mg, 60%).

MS (ESI, pos. ion) m/z: 626.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.78-8.65 (m, 2H), 8.33 (d, J=1.8 Hz,1H), 8.14 (d, J=8.4 Hz, 2H), 8.11 (d, J=8.2 Hz, 2H), 7.60-7.47 (m, 3H),7.31 (s, 2H), 6.75 (s, 1H), 5.19 (s, 1H), 4.56 (s, 1H), 3.75 (s, 3H),2.46 (d, J=5.4 Hz, 1H), 2.39 (s, 3H), 2.11 (d, J=2.3 Hz, 1H), 1.99 (s,1H), 1.92-1.78 (m, 2H), 1.77-1.60 (m, 5H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(215 mg, 0.3 mmol) in 1,4-dioxane (5 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 0.6 mL, 2.4 mmol). The mixturewas stirred at 70° C. overnight. After the reaction was completed, themixture was diluted with ethyl acetate (10 mL), and the mixture waswashed with saturated aqueous sodium bicarbonate (20 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=15/1) to give the title compound as a light yellowsolid (125 mg, 77%).

MS (ESI, pos. ion) m/z: 472.2 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.78 (s, 1H), 8.64 (d, J=9.3 Hz, 1H),8.34 (s, 1H), 7.84 (d, J=4.8 Hz, 2H), 7.64 (s, 3H), 6.74 (s, 1H), 5.12(s, 1H), 3.66 (s, 3H), 2.74 (d, J=5.7 Hz, 1H), 2.12 (s, 1H), 1.77 (m,9H), 1.30 (s, 2H).

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(285 mg, 0.60 mmol) in a mixed solvent of methanol (2 mL), THF (2 mL)and water (2 mL) was added sodium hydroxide (250 mg, 6.25 mmol). Themixture was stirred at rt overnight. After the reaction was completed,the mixture was concentrated in vacuo to remove the organic solvent. Theresidue was diluted with 2-methyl tetrahydrofuran (10 mL), and themixture was was adjusted with diluted hydrochloric acid (1 M) to pH5.5-6.0. The resulting mixture was extracted with 2-methyltetrahydrofuran (15 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=50/1) to give the title compound as a light yellow solid(120 mg, 43%).

MS (ESI, pos. ion) m/z: 458.3 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.64 (s, 1H), 8.39 (d,J=2.2 Hz, 1H), 8.29 (s, 1H), 8.11 (s, 2H), 7.64-7.41 (m, 4H), 6.76 (s,1H), 4.65 (s, 1H), 2.01 (m, 2H), 1.81 (m, 2H), 1.46 (m, 8H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 175.94, 162.91, 162.39, 156.77,155.25, 154.46, 146.46, 138.34, 131.76, 131.36, 130.31, 129.23, 126.76,119.05, 115.41, 114.21, 98.26, 31.75, 29.54, 28.51, 24.18, 22.56, 21.38,19.43.

Example 4a:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared by the synthetic method disclosed inpatent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 2 of example 4, using (2S,3S)-ethyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (316 mg, 1.35mmol), 2,4-dicholoro-6-phenylpyrimidine (334 mg, 1.49 mmol), potassiumcarbonate (560 mg, 4.05 mmol) as reagents and DMF (6 mL) as solvent. Thetitle compound was a light yellow solid (291 mg, 56%).

Step 3: (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 3 of example 4, using (2S,3S)-ethyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (291 mg, 0.75 mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(437 mg, 1.05 mmol), potassium carbonate (207 mg, 1.50 mmol),Pd(dppf)Cl₂ (58 mg, 0.08 mmol), 1,4-dioxane (5 mL) and water (0.5 mL),the title compound is a light yellow solid (249 mg, 52%).

Step 4:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(249 mg, 0.39 mmol) in THF/MeOH (v/v=1/1, 6 mL) was added aqueous sodiumhydroxide solution (4 M, 0.98 mL, 3.90 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were dried over anhydrous sodium sulfate,then filtered. The filtrate was concentrated in vacuo and the residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1)to give the title compound as a yellow solid (109 mg, 61%).

MS (ESI, pos. ion) m/z: 458.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 458.1983[M+H]⁺, (C₂₆H₂₅FN₅O₂)[M+H]⁺theoretical value: 458.1992;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.63 (s, 1H), 8.39 (s,1H), 8.29 (s, 1H), 8.10 (s, 2H), 7.53 (m, 4H), 6.77 (s, 1H), 4.65 (s,1H), 1.99 (s, 2H), 1.81 (s, 2H), 1.74-1.54 (m, 4H), 1.47-1.39 (m, 2H).

Example 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl) amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(2-fluorophenyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (3.0 mL, 25.57 mmol) in THF(20 mL) were added palladium acetate (0.1 g, 0.4 mmol),triphenylphosphine (0.24 g, 0.87 mmol), 2-fluorophenylboronic acid (3 g,21 mmol) and aqueous sodium carbonate solution (1 M, 43 mL, 43 mmol).The mixture was stirred at 60° C. for 4 h under nitrogen protection.After the reaction was completed, the mixture was cooled to rt, andconcentrated in vacuo. To the residue was added H₂O (100 mL), and theresulting mixture was extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with saturated brine (100 mL), driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE) to give the title compound as a white solid (3.5 g,67%).

MS (ESI, pos. ion) m/z: 243.1 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of 2,4-dichloro-6-(2-fluorophenyl)pyrimidine (2.01 g, 8.2mmol) and (+/−)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate(1.50 g, 8.2 mmol) in N,N-dimethylformamide (10 mL) was added potassiumcarbonate (1.10 g, 8 mmol). The mixture was stirred at rt overnight.After the reaction was completed, to the mixture was added H₂O (40 mL),and the resulting mixture was extracted with ethyl acetate (40 mL×3).The combined organic layers were washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (n-hexane) to give the title compound as a white solid(2.26 g, 71%).

MS (ESI, pos. ion) m/z: 390.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.11 (td, J=7.8, 1.6 Hz, 1H), 7.44 (td,J=7.3, 1.7 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.16 (dd, J=11.6, 8.3 Hz,1H), 6.89 (s, 1H), 5.37 (d, J=4.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.76 (s,3H), 2.39 (d, J=5.3 Hz, 1H), 2.06 (s, 1H), 1.88 (d, J=2.6 Hz, 1H),1.82-1.61 (m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixed solvent of 1,4-dioxane (15 mL) and H₂O (0.5 mL) were added(+/−)-trans-methyl3-((2-chloro-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(590 mg, 1.51 mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(630 mg, 1.51 mmol), potassium carbonate (419 mg, 3.03 mmol) andPd(dppf)Cl₂ (124 mg, 0.15 mmol). The air in the mixture was removed byby bubbling with nitrogen for 10 min, and then stirred at 110° C.undergoing a microwave reaction for 1 h. The mixture was filteredthrough a celite pad, and the filter cake was washed with ethyl acetate(20 mL). The combined filtrates was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=15/1) to give the title compound as a yellow solid (500 mg, 51%).

MS (ESI, pos. ion) m/z: 644.2 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.71 (s, 1H), 8.66 (dd, J=8.8, 2.6 Hz,1H), 8.33 (d, J=1.9 Hz, 1H), 8.22-8.18 (m, 1H), 8.13 (d, J=8.1 Hz, 2H),7.46 (dd, J=12.2, 6.5 Hz, 1H), 7.39 (s, 1H), 7.36 (s, 2H), 7.35 (s, 1H),7.30 (s, 1H), 6.83 (s, 1H), 4.95 (s, 1H), 4.73 (s, 1H), 3.81 (s, 3H),3.75 (s, 3H), 3.62 (s, 1H), 2.46 (d, J=4.9 Hz, 1H), 2.42 (d, J=5.0 Hz,1H), 2.10 (d, J=2.1 Hz, 1H), 2.00 (s, 1H), 1.60 (d, J=14.8 Hz, 1H),1.53-1.47 (m, 1H), 1.41-1.38 (m, 1H), 1.37 (d, J=1.3 Hz, 1H), 1.19 (s,1H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL, 40 mmol)was added (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (380 mg, 0.59mmol). The mixture was stirred at 65° C. for 4 h. After the reaction wascompleted, the mixture was concentrated, and the residue was dilutedwith ethyl acetate (10 mL). The mixture was washed with saturatedaqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). Theorganic layer was dried over anhydrous sodium sulfate and filtered, thenthe filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (n-hexane/EtOAc (v/v)=5/1) to give thetitle compound as a brown solid (352 mg, 75%).

MS (ESI, pos. ion) m/z: 490.3 [M+H]⁺.

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(130 mg, 0.26 mmol) in a mixed solvent of methanol (3 mL), THF (3 mL)and water (3 mL) was added sodium hydroxide (107 mg, 2.67 mmol). Themixture was stirred at rt overnight. After the reaction was completed,the mixture was concentrated in vacuo to remove the organic solvent, andthe residue was diluted with 2-methyl tetrahydrofuran (10 mL). Themixture was adjusted with diluted hydrochloric acid (1 mol/L) to pH 5.5.The resulting mixture was extracted with 2-methyl tetrahydrofuran (15mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=1/1) to give the title compound as a light yellow solid (93 mg,74%).

MS (ESI, pos. ion) m/z: 476.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.13 (s, 1H), 8.70 (dd, J=9.2, 2.4 Hz,1H), 8.59 (s, 1H), 8.25 (t, J=7.1 Hz, 1H), 8.04 (s, 1H), 7.45 (dd,J=12.9, 5.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.18 (dd, J=11.5, 8.3 Hz,1H), 6.78 (s, 1H), 5.30 (s, 1H), 4.90 (s, 1H), 2.56 (s, 1H), 2.20 (s,1H), 1.95-1.65 (m, 10H).

Example 6:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(4-fluorophenyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (6.3 mL, 54 mmol) in THF (35mL) were added palladium acetate (0.16 g, 0.70 mmol), triphenylphosphine(0.39 g, 1.4 mmol), p-fluorophenylboronic acid (5 g, 36 mmol) andaqueous sodium carbonate solution (1 mol/L, 71 mL, 71 mmol). The mixturewas stirred at 60° C. under nitrogen protection for 6 h. After thereaction was completed, the mixture was cooled to rt, and concentratedin vacuo. To the residue was added H₂O (100 mL), and the resultingmixture was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with saturated brine (300 mL), dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography (PE)to give the title compound as a white solid (8.01 g, 92%).

MS (ESI, pos. ion) m/z: 242.9 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of 2,4-dichloro-6-(4-fluorophenyl)pyrimidine (2.01 g, 8.2mmol) and (+/−)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate(1.50 g, 8.2 mmol) in N,N-dimethylformamide (10 mL) was added potassiumcarbonate (1.10 g, 8 mmol). The mixture was stirred at rt overnight. Tothe reaction mixture was added water (40 mL), and the resulting themixture was extracted with ethyl acetate (40 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (n-hexane)to give the title compound as a white solid (1.75 g, 55%).

MS (ESI, pos. ion) m/z: 390.1 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixed solvent of 1,4-dioxane (15 mL) and H₂O (0.5 mL) were added(+/−)-trans-methyl3-((2-chloro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(600 mg, 1.54 mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(640 mg, 1.53 mmol), potassium carbonate (426 mg, 3.08 mmol),Pd(dppf)Cl₂ (126 mg, 0.15 mmol). The mixture in microwave tube wasstirred at 110° C. undergoing a microwave reaction for 1 h undernitrogen protection. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (20 mL). The combinedfiltrates were concentrated in vacuo, and the residue was purified bysilica gel column chromatography (n-hexane/EtOAc (v/v)=15/1) to give thetitle compound as a yellow solid (500 mg, 51%).

MS (ESI, pos. ion) m/z: 644.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.72 (s, 1H), 8.66 (dd, J=8.8, 2.7 Hz,1H), 8.34 (s, 1H), 8.17-8.06 (m, 4H), 7.31 (s, 2H), 7.23 (t, J=8.6 Hz,2H), 6.70 (s, 1H), 3.74 (s, 3H), 3.51 (s, 1H), 2.45 (d, J=5.1 Hz, 1H),2.43 (d, J=3.8 Hz, 1H), 2.39 (s, 3H), 2.13 (s, 2H), 1.99 (s, 2H), 1.93(s, 2H), 1.85 (d, J=11.3 Hz, 2H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of of hydrogen chloride in 1,4-dioxane (4 M, 10 mL, 40mmol) was added (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(620 mg, 0.96 mmol). The mixture was stirred at 65° C. for 4 h. Afterthe reaction was completed, the mixture was concentrated in vacuo, andthe residue was diluted with ethyl acetate (20 mL). The resultingmixture was washed with saturated aqueous sodium bicarbonate (20 mL) andsaturated brine (20 mL). The organic layer was dried over anhydroussodium sulfate and filtered, then the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a light yellowsolid (352 mg, 75%).

MS (ESI, pos. ion) m/z: 490.3 [M+H]⁺.

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-fluorophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(352 mg, 0.72 mmol) in a mixed solvent of methanol (5 mL), THF (5 mL)and water (2 mL) was added sodium hydroxide (290 mg, 7.25 mmol). Themixture was stirred at rt overnight. After the reaction was completed,the mixture was concentrated in vacuo, and the residue was diluted with2-methyl tetrahydrofuran (10 mL). The mixture was adjusted with dilutedhydrochloric acid (1 M) to pH 5.5. The resulting mixture was extractedwith 2-methyl tetrahydrofuran (15 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=1/1) to give the title compound asa light yellow solid (241 mg, 70%).

MS (ESI, pos. ion) m/z: 476.4 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.77 (dd, J=9.6, 2.5 Hz, 1H), 8.41 (s,1H), 8.18 (s, 1H), 8.12 (dd, J=8.7, 5.5 Hz, 2H), 7.26 (t, J=8.7 Hz, 2H),6.74 (s, 1H), 2.59 (d, J=4.5 Hz, 1H), 2.09 (s, 1H), 2.04 (d, J=6.0 Hz,2H), 1.93-1.54 (m, 8H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 175.72, 165.03, 163.23, 162.76,158.21, 157.11, 155.48, 151.94, 146.36, 139.67, 130.12, 128.51, 125.38,118.92, 116.40, 116.26, 73.99, 60.43, 50.98, 49.45, 34.85, 30.89, 25.42,21.50.

Example 7:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloropyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (15 mL) were added (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (405 mg, 2.21 mmol),2,4-dichloropyrido[2,3-d]pyrimidine (401 mg, 2.00 mmol) and potassiumphosphate (1.28 g, 6.03 mmol). The mixture was stirred at 80° C.overnight under nitrogen protection. The mixture was filtered through acelite pad, and the filter cake was washed with ethyl acetate (30 mL).The combined filtrates were concentrated in vacuo, and the residue waspurified by silica gel chromatography (PE/MeOH (v/v)=2/1−1/2) to givethe title compound as a light yellow solid (676 mg, 97%).

MS (ESI, pos. ion) m/z: 347.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.97-8.89 (m, 1H), 8.48 (d, J=7.2 Hz,1H), 7.32 (dd, J=8.2, 4.4 Hz, 1H), 7.11 (s, 1H), 4.71 (s, 1H), 3.76 (s,3H), 2.65 (d, J=4.3 Hz, 1H), 2.05 (d, J=2.3 Hz, 1H), 1.99 (s, 1H), 1.85(d, J=11.0 Hz, 2H), 1.73-1.54 (m, 5H), 1.45 (m, 1H).

Step 2: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixed solvent of 2-methyltetrahydrofuran (5 mL) and water (1 mL)were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(223 mg, 0.53 mmol), K₃PO₄ (190 mg, 0.90 mmol), Pd₂(dba)₃ (42 mg, 0.05mmol), (+/−)-trans-methyl3-((2-chloropyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(155 mg, 0.45 mmol) and X-phos (22 mg, 0.05 mmol). The mixture wasstirred at 78° C. overnight under nitrogen protection. The mixture wasdiluted with ethyl acetate (40 mL), and the resulting mixture wasfiltered through a celite pad. The filtrate was partitioned, and theorganic layer was concentrated in vacuo, and then the residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1-20/1)to give the title compound as light yellow foam (96 mg, 36%).

MS (ESI, pos. ion) m/z: 601.3 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 9.07 (dd, J=4.3, 1.6 Hz, 1H), 8.93 (dd,J=8.7, 2.8 Hz, 1H), 8.90 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.17 (d, J=8.4Hz, 2H), 8.14 (dd, J=8.1, 1.5 Hz, 1H), 7.38 (dd, J=8.1, 4.4 Hz, 1H),7.31 (d, J=8.2 Hz, 2H), 5.99 (d, J=6.4 Hz, 1H), 5.01 (s, 1H), 3.75 (s,3H), 2.54 (d, J=5.5 Hz, 1H), 2.40 (s, 3H), 2.17-2.11 (m, 2H), 2.02-1.97(m, 1H), 1.77-1.72 (m, 3H), 1.65 (m, 4H).

Step 3:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(92 mg, 0.15 mmol) in THF/MeOH/H₂O (v/v/v=1/1/1, 3 mL) was added sodiumhydroxide (62 mg, 1.55 mmol). The mixture was stirred at rt overnight,then the mixture was diluted with water (15 mL), and the resultingmixture was acidified with hydrochloric acid (1 M) to pH about 6.0. Themixture was stirred at rt for 30 min, and filtered to give the titlecompound as a brown solid (45 mg, 68%).

MS (ESI, pos. ion) m/z: 433.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 8.93 (d, J=5.7 Hz,2H), 8.71 (d, J=7.7 Hz, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H),7.46 (d, J=5.1 Hz, 1H), 4.94 (s, 1H), 3.01 (d, J=5.9 Hz, 1H), 2.07 (s,2H), 1.92-1.80 (m, 3H), 1.72-1.40 (m, 5H).

Example 8:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)-4,4-dimethylpentanoicacid

Step 1: (R)-methyl 3-amino-4,4-dimethylpentanoate

To a solution of (R)-3-amino-4,4-dimethylpentanoic acid (1.01 g, 6.96mmol) in methanol (60 mL) was added dropwise slowly oxalyl chloride (0.9mL, 10 mmol) at 0° C., and the mixture was stirred for 1 h maintainingat this temperature. The mixture was heated to 65° C. and stirred for 2h. The mixture was concentrated in vacuo to dry, then the residue waswashed with toluene (30 mL×3) and filtered to give the title compound asa white solid (1.11 g, 99%).

MS (ESI, pos. ion) m/z: 160.3 [M+H]⁺.

Step 2: (R)-methyl3-((2-chloroquinazolin-4-yl)amino)-4,4-dimethylpentanoate

To a solution of (R)-methyl 3-amino-4,4-dimethylpentanoate (700 mg, 4.39mmol) in tetrahydrofuran (20 mL) were added DIPEA (3.63 mL, 22.0 mmol)and 2,4-dichloroquinazoline (875 mg, 4.39 mmol). The mixture was stirredat rt overnight. The mixture was concentrated in vacuo and the residuewas purified by silica gel chromatography (PE/EtOAc (v/v)=5/1) to givethe title compound as a white solid (907 mg, 64%).

MS (ESI, pos. ion) m/z: 322.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.74 (m, 2H), 7.48 (dd, J=11.3,5.0 Hz, 1H), 6.93 (d, J=9.5 Hz, 1H), 4.85 (ddd, J=9.7, 6.8, 4.9 Hz, 1H),3.68 (s, 3H), 2.74 (dd, J=15.1, 4.8 Hz, 1H), 2.64 (dd, J=15.1, 6.9 Hz,1H), 1.05 (s, 9H).

Step 3: (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)-4,4-dimethylpentanoate

To a mixed solvent of 1,4-dioxane (8 mL) and water (1 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(400 mg, 0.62 mmol), potassium carbonate (155 mg, 1.12 mmol),Pd(dppf)Cl₂ (45 mg, 0.05 mmol) and (R)-methyl3-((2-chloroquinazolin-4-yl)amino)-4,4-dimethylpentanoate (180 mg, 0.56mmol). The mixture was degassed for 10 minutes by nitrogen bubbling. Themixture in a sealed tube was stirred at 110° C. for 2 hours. The mixturewas diluted with ethyl acetate (20 mL), and the resulting mixture wasfiltered through a celite pad. The filtrate was partitioned and theorganic layer was concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=6/1) to give the titlecompound as a yellow solid (200 mg, 62%).

MS (ESI, pos. ion) m/z: 644.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.85 (dd, J=9.0, 2.8 Hz, 1H), 8.34 (d,J=1.9 Hz, 1H), 8.14 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.0 Hz, 1H), 7.76 (t,J=7.6 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 6.37 (d,J=9.4 Hz, 1H), 5.06 (ddd, J=9.2, 7.5, 5.1 Hz, 1H), 3.59 (s, 3H), 2.82(dd, J=14.8, 4.9 Hz, 1H), 2.68 (dd, J=14.8, 7.5 Hz, 1H), 2.39 (s, 3H),1.12 (s, 9H).

Step 4:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)-4,4-dimethylpentanoic acid

To a solution of (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl)amino)-4,4-dimethylpentanoate (190 mg, 0.33 mmol) inTHF/MeOH (v/v=1/1, 4 mL) was added aqueous sodium hydroxide solution (4M, 0.83 mL, 3.33 mmol). The mixture was stirred at 30° C. overnight,then diluted with water (10 mL). The resulting mixture was acidifiedwith hydrochloric acid (1 M) to pH about 6.0, then extracted with ethylacetate (15 mL×3). The combined organic layers were washed withsaturated brine (40 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as awhite solid (55 mg, 41%).

MS (ESI, pos. ion) m/z: 408.3 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.33 (s, 1H), 8.82 (d, J=9.6 Hz,1H), 8.42 (d, J=7.5 Hz, 2H), 8.31 (s, 1H), 7.75 (s, 2H), 7.43 (s, 1H),5.16 (m, 1H), 2.75 (d, J=14.6 Hz, 1H), 2.70-2.63 (m, 1H), 1.03 (s, 9H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 173.83, 160.54, 158.60, 156.92,155.33, 146.52, 133.17, 131.90, 131.71, 124.61, 123.58, 119.17, 119.12,116.21, 116.07, 113.52, 55.86, 36.15, 35.86, 27.14.

Example 9:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(furan-2-yl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) in THF (4mL) were added tetrakis(triphenylphosphine)palladium (43 mg, 0.05 mmol),2-furylboronic acid (61 mg, 0.55 mol) and aqueous sodium bicarbonatesolution (1 M, 1.64 mL, 1.64 mmol). The mixture was stirred at 80° C.overnight under nitrogen protection. To the reaction mixture was addedwater (50 mL), and the resulting mixture was extracted with ethylacetate (50 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE) to give the titlecompound as a green solid (42 mg, 36%).

MS (ESI, pos. ion) m/z: 215.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (d, J=0.7 Hz, 1H), 7.58 (s, 1H),7.43 (d, J=3.4 Hz, 1H), 6.65 (dd, J=3.4, 1.6 Hz, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (429 mg, 2.34 mmol) and2,4-dichloro-6-(furan-2-yl)pyrimidine (420 mg, 1.95 mmol) in DMF (5 mL)were added potassium carbonate (809 mg, 5.86 mmol). Then the mixture wasstirred at room temperature overnight. Water (40 mL) was added to themixture and the resulting mixture was extracted with EtOAc (40 mL×3).The combined organic layers were washed with saturated brine (100 mL),dried over anhydrous Na₂SO₄ and filtered, then the filtrate wasconcentrated in vacuo. The residue obtained was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=5/1) to give the title compound asa white solid (383 mg, 54%).

MS (ESI, pos. ion) m/z: 362.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.56 (s, 1H), 7.22 (s, 1H), 6.93 (s,1H), 6.55 (d, J=1.6 Hz, 1H), 5.47 (d, J=5.5 Hz, 1H), 4.44 (s, 1H), 3.70(s, 3H), 2.44-2.33 (m, 1H), 1.96 (d, J=2.5 Hz, 1H), 1.88 (s, 1H),1.84-1.58 (m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A microwave tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(276 mg, 0.33 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.28 mmol), potassium carbonate (114 mg, 0.83 mmol),Pd(dppf)Cl₂ (45 mg, 0.06 mmol), 1,4-dioxane (3 mL) and H₂O (0.2 mL). Theresulting solution was bubbled with nitrogen for 10 minutes to removethe air and then the mixture in the tube was subjected to a microwavereaction at 110° C. for 2 h. The reaction mixture was passed through acelite and the filter cake was washed with EtOAc (50 mL). The filtratewas washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄,filtered, and the filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (72 mg, 42%).

MS (ESI, pos. ion) m/z: 616.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.70-8.64 (m, 2H), 8.33 (d, J=2.0 Hz,1H), 8.12 (d, J=8.3 Hz, 2H), 7.59 (s, 1H), 7.30 (s, 1H), 7.26 (d, J=3.2Hz, 1H), 6.67 (s, 1H), 6.60 (dd, J=3.3, 1.7 Hz, 1H), 4.76 (s, 1H), 3.75(s, 3H), 2.45 (s, 1H), 2.39 (s, 3H), 2.10 (s, 1H), 1.98 (s, 1H), 1.42(m, 8H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(75 mg, 0.12 mmol) in THF/MeOH (v/v=1/1, 4 mL) was added NaOH aqueoussolution (4 M, 0.30 mL, 1.20 mmol) and the resulting mixture was stirredovernight at 30° C. Water (10 mL) was added to the mixture and theresulting mixture was adjusted with HCl (1 M) to pH about 5.5. Then themixture was extracted with EtOAc (20 mL×3). The organic layers werecombined, washed with saturated brine (50 mL), dried over anhydrousNa₂SO₄, filtered, and the filtrate was concentrated in vacuo. Theresidue obtained was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a yellow solid (35mg, 64%).

MS (ESI, pos. ion) m/z: 472.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 448.1776 [M+H]⁺, (C₂₄H₂₃FN₅O₃)[M+H]⁺theoretical value: 448.1785;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.60 (s, 1H), 8.32 (s,1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 6.69 (s,1H), 6.63 (s, 1H), 4.62 (s, 1H), 1.99 (s, 2H), 1.83-1.33 (m, 10H).

Example 9a:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 2 of example 9, using (2S,3S)-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (331 mg, 1.42mmol), 2,4-dicholoro-6-(furan-2-yl)pyrimidine (278 mg, 1.29 mmol),potassium carbonate (590 mg, 4.26 mmol) as reagents and DMF (6 mL) assolvent. The title compound was a light yellow solid (247 mg, 51%).

Step 3: (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 3 of example 9, using (2S,3S)-ethyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(78 mg, 0.21 mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(203 mg, 0.29 mmol, 60%), potassium carbonate (87 mg, 0.63 mmol),Pd(dppf)Cl₂ (15 mg, 0.02 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The title compound was a light yellow solid (81 mg, 61%).

Step 4:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(81 mg, 0.13 mmol) in THF/EtOH (v/v=1/1, 4 mL) was added aqueous sodiumhydroxide solution (4 M, 0.33 mL, 1.30 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were dried over anhydrous sodium sulfate,then filtered. The filtrate was concentrated in vacuo and the residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1)to give the title compound as a yellow solid (35 mg, 64%).

MS (ESI, pos. ion) m/z: 448.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 448.1763 [M+H]⁺, (C₂₄H₂₃FN₅O₃)[M+H]⁺theoretical value: 448.1785;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.29 (s, 1H), 8.62 (s, 1H), 8.33 (s,1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 6.69 (s,1H), 6.65 (s, 1H), 4.63 (s, 1H), 1.99 (s, 2H), 1.80-1.38 (m, 8H).

Example 10:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(2-phenylethynyl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (101 mg, 0.55 mmol) intoluene (3 mL) was added tributyl(2-phenylethynyl)stannane (259 mg, 0.66mmol), triphenylarsine (67 mg, 0.22 mmol), Pd(PPh₃)Cl₂ (40 mg, 0.06mmol). The reaction mixture was heated to 80° C. and stirred for 6 hunder nitrogen protection. The mixture was concentrated in vacuo and theobtained residue was purified by silica gel column chromatography (PE)to give the title compound as a white solid (129 mg, 94%).

MS (ESI, pos. ion) m/z: 249.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (t, J=7.9 Hz, 2H), 8.29 (d, J=8.7Hz, 1H), 7.88-7.74 (m, 2H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (405 mg, 2.21 mmol) and2,4-dichloro-6-(phenylethynyl)pyrimidine (500 mg, 2.01 mmol) in DMF (5mL) was added potassium carbonate (306 mg, 2.21 mmol). Then the mixturewas stirred at room temperature overnight. Water (40 mL) was added tothe mixture and the resulting mixture was extracted with EtOAc (40mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The obtainedresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=5/1) to give the title compound as a white solid (470 mg, 59%).

MS (ESI, pos. ion) m/z: 396.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.59 (d, J=6.8 Hz, 2H), 7.41-7.37 (m,3H), 6.55 (s, 1H), 5.50 (s, 1H), 3.76 (s, 3H), 2.36 (d, J=5.3 Hz, 1H),1.84 (s, 1H), 1.70-1.42 (m, 10H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A microwave tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(253 mg, 0.30 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.25 mmol), potassium carbonate (105 mg, 0.76 mmol),Pd(dppf)Cl₂ (42 mg, 0.05 mmol), 1,4-dioxane (3 mL) and H₂O (0.2 mL). Theresulting mixture was bubbled with nitrogen for 3 minutes to remove theair and then the mixture in the tube was subjected to a microwavereaction at 110° C. for 2 h. The reaction mixture was passed through acelite and the filter cake was washed with EtOAc (50 mL). The combinedorganic layers were washed with saturated brine (50 mL), dried overanhydrous Na₂SO₄ and filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(37 mg, 23%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.70 (s, 1H), 8.65 (dd, J=8.8, 2.7 Hz,1H), 8.32 (s, 1H), 8.12 (d, J=8.3 Hz, 2H), 7.73 (dd, J=5.6, 3.4 Hz, 2H),7.69-7.63 (m, 2H), 7.55 (dd, J=5.6, 3.3 Hz, 2H), 7.43 (s, 1H), 7.31 (s,1H), 6.52 (s, 1H), 3.81 (s, 1H), 3.75 (s, 3H), 2.42 (s, 1H), 2.39 (s,3H), 2.11 (s, 1H), 1.97 (s, 1H), 1.80-1.64 (m, 8H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(37 mg, 0.06 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added NaOH aqueoussolution (4 M, 0.15 mL, 0.60 mmol) and the mixture was stirred overnightat 30° C. Water (10 mL) was added to the mixture and the resultingmixture was adjusted with HCl (1 M) to pH about 5.5, then extracted withEtOAc (20 mL×3). The combined organic layers were washed with saturatedbrine, dried over anhydrous Na₂SO₄ and filtered, then the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as ayellow solid (19 mg, 69%).

MS (ESI, pos. ion) m/z: 482.5 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.33 (s, 1H), 8.60 (s, 1H), 8.43 (s,1H), 8.38 (t, J=9.5 Hz, 4H), 8.30 (s, 1H), 7.66 (s, 1H), 6.88 (s, 1H),4.71 (s, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 1.44 (s, 8H).

Example 10a:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 2 of example 10, using (2S,3S)-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (386 mg, 1.65mmol), 2,4-dichloro-6-(phenylethynyl)pyrimidine (410 mg, 1.65 mmol),potassium carbonate (684 mg, 4.95 mmol) as reagents and DMF (5 mL) assolvent. The title compound was a yellow solid (458 mg, 68%).

MS (ESI, pos. ion) m/z: 410.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.63-7.57 (m, 2H), 7.43-7.36 (m, 3H),6.57 (s, 1H), 5.50 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.34 (d, J=5.1 Hz,1H), 2.09 (s, 1H), 1.85 (d, J=2.4 Hz, 1H), 1.78-1.63 (m, 6H), 1.57 (d,J=9.8 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

Step 3: (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 3 of example 10, using5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(541 mg, 0.59 mmol, 45%), (2S,3S)-ethyl 3-((2-chloro-6-(phenylethynylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.49mmol), potassium carbonate (202 mg, 1.46 mmol) and Pd(dppf)Cl₂ (79 mg,0.10 mmol) as reagents, and a mixture of 1,4-dioxane (3 mL) and water(0.2 mL) as mixed solvent. The title compound was a yellow solid (46 mg,14%).

MS (ESI, pos. ion) m/z: 664.2[M+H]⁺.

Step 4:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(2-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

The title compound can be prepared by the synthetic method described instep 4 of example 10, using (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(46 mg, 0.07 mmol), a aqueous NaOH solution (4 M, 0.18 mL, 0.70 mmol),and mixed solvent THF/MeOH(v/v=1/1, 2 mL). The title compound was ayellow solid (10 mg, 30%).

MS (ESI, pos. ion) m/z: 482.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.35 (s, 1H), 8.56 (d, J=8.6 Hz,1H), 8.28 (s, 2H), 7.93 (s, 1H), 7.64 (s, 2H), 7.49 (s, 3H), 6.58 (s,1H), 4.64 (s, 1H), 2.56 (s, 1H), 1.87-1.49 (m, 10H).

Example 11:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenoxypyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-6-phenoxypyrimidine

To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) inacetone (6 mL) were added dropwise slowly a mixture of phenol (257 mg,2.73 mmol) and NaOH (112 mg, 2.78 mmol) at 0° C. The mixture was stirredfor 3 h at room temperature. Then 30 mL of H₂O was added to the mixture.The resulting mixture was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with saturated brine (50 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as colourless oil (569 mg, 87%).

MS (ESI, pos. ion) m/z: 249.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.48 (t, J=8.0 Hz, 2H), 7.34 (t, J=7.5Hz, 1H), 7.18-7.14 (m, 2H), 6.80 (s, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-phenoxypyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (460 mg, 2.51 mmol) and2,4-dichloro-6-phenoxy-pyrimidine (550 mg, 2.28 mmol) in DMF (5 mL) wasadded potassium carbonate (346 mg, 2.51 mmol). Then the mixture wasstirred at room temperature overnight. Water (40 mL) was added to themixture and the resulting mixture was extracted with EtOAc (40 mL×3).The combined organic layers were washed with saturated brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=1/1)to give the title compound as a white solid (386 mg, 44%).

MS (ESI, pos. ion) m/z: 388.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.59 (d, J=6.8 Hz, 2H), 7.41-7.37 (m,3H), 6.55 (s, 1H), 5.50 (s, 1H), 3.76 (s, 3H), 2.36 (d, J=5.3 Hz, 1H),1.84 (s, 1H), 1.70-1.42 (m, 10H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenoxypyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A sealed tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(258 mg, 0.31 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-phenoxypyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.26 mmol), potassium carbonate (106 mg, 0.77 mmol),Pd(dppf)Cl₂ (42 mg, 0.05 mmol), 1,4-dioxane (3 mL) and H₂O (0.2 mL). Theresulting mixture in the sealed tube was stirred at 110° C. for 3 hunder nitrogen protection. The reaction mixture was passed through acelite and the filter cake was washed with EtOAc (50 mL). The filtratewas washed with saturated brine (50 mL), dried over Na₂SO₄ and filtered,and the filtrate was concentrated in vacuo to dry. The residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (80 mg, 48%).

MS (ESI, pos. ion) m/z: 642.6[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.45 (s, 1H), 8.34 (s, 1H), 8.28 (s,1H), 8.10 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.8 Hz, 2H), 7.31 (d, J=8.3 Hz,3H), 7.20 (d, J=7.8 Hz, 2H), 6.39 (s, 1H), 5.16 (s, 1H), 4.64 (s, 1H),3.64 (s, 3H), 2.40 (s, 3H), 2.32 (d, J=6.3 Hz, 1H), 2.01 (s, 1H), 1.71(d, J=11.5 Hz, 2H), 1.55-1.30 (m, 6H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenoxypyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-phenoxypyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(173 mg, 0.27 mmol) in a mixed solvent THF/MeOH (v/v=1/1, 3 mL) wasadded NaOH aqueous solution (4 M, 0.67 mL, 2.70 mmol), and the mixturewas stirred overnight at 30° C. Water (10 mL) was added to the mixtureand the resulting mixture was adjusted with HCl (1 M) to pH about 5.5.Then the mixture was extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with saturated brine, dried over anhydrousNa₂SO₄ and filtered, then the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a yellow solid (70 mg, 55%).

MS (ESI, pos. ion) m/z: 474.1 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.37 (s, 1H), 12.20 (s, 1H), 8.50(s, 1H), 8.29 (s, 1H), 7.43 (s, 2H), 7.29-7.17 (m, 3H), 7.10 (d, J=5.0Hz, 1H), 6.73 (s, 1H), 4.55 (s, 1H), 3.60 (s, 1H), 3.36 (s, 3H), 2.68(s, 1H), 1.77 (m, 8H).

Example 12:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) in THF (4mL) were added Pd(PPh₃)₂Cl₂ (38 mg, 0.05 mmol),(1-methylpyrazol-4-yl)boronic acid (68 mg, 0.55 mol) and Na₂CO₃ aqueoussolution (1 M, 1.10 mL, 1.10 mmol). The reaction mixture was heated to70° C. under nitrogen protection and stirred for 4 h. Then 50 mL ofwater was added to the mixture. The mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous Na₂SO₄ and filtered, then the filtrate wasconcentrated in vacuo to dry. The residue was purified by silica gelcolumn chromatography (n-hexane/EtOAc (v/v)=5/1) to give the titlecompound as a white solid (94 mg, 75%).

MS (ESI, pos. ion) m/z: 229.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.12 (s, 1H), 8.03 (s, 1H), 7.34 (s,1H), 4.00 (s, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (88 mg, 0.48 mmol),2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine (92 mg, 0.40 mmol)in DMF (2 mL) was added potassium carbonate (167 mg, 1.20 mmol). Thenthe mixture was stirred at room temperature overnight. Water (40 mL) wasadded to the mixture and the resulting mixture was extracted with EtOAc(40 mL×3). The combined organic layers were washed with saturated brine(100 mL), dried over anhydrous Na₂SO₄ and filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/1) to give the title compound as awhite solid (87 mg, 58%).

MS (ESI, pos. ion) m/z: 376.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (s, 1H), 7.94 (s, 1H), 6.52 (s,1H), 5.37 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 2.38 (d, J=5.0 Hz, 1H),2.07 (d, J=5.7 Hz, 1H), 1.86 (d, J=2.6 Hz, 1H), 1.49 (m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A microwave tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(231 mg, 0.28 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-(1-methylpyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(87 mg, 0.23 mmol), potassium acetate (95 mg, 0.69 mmol), Pd(dppf)Cl₂(37 mg, 0.05 mmol), 1,4-dioxane (3 mL) and H₂O (0.2 mL). The resultingmixture was bubbled with nitrogen for 10 minutes and then the mixturewas stirred at 110° C. with microwave heating for 2 h. The reactionmixture was filtered through a celite pad and the filter cake was washedwith EtOAc (50 mL). The filtrate was washed with saturated brine (50mL), dried over Na₂SO₄ and filtered, and the filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a brown solid(54 mg, 37%).

MS (ESI, pos. ion) m/z: 630.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66 (s, 1H), 8.63 (dd, J=8.9, 2.6 Hz,1H), 8.33 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 8.06 (s, 1H), 8.01 (s, 1H),7.30 (s, 1H), 6.47 (s, 1H), 5.15 (s, 1H), 4.49 (s, 1H), 4.03 (s, 3H),3.74 (s, 3H), 2.43 (d, J=5.1 Hz, 1H), 2.39 (s, 3H), 2.10 (s, 1H), 1.97(s, 1H), 1.52-1.39 (m, 8H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(54 mg, 0.09 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added NaOH aqueoussolution (4 M, 0.23 mL, 0.90 mmol), and the mixture was stirredovernight at 30° C. Water (10 mL) was added to the mixture and theresulting mixture was adjusted with HCl (1M) to pH about 5.5. Then themixture was extracted with EtOAc (20 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo. The residue obtained was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=10/1) to give the title compoundas a yellow solid (17 mg, 43%).

MS (ESI, pos. ion) m/z: 462.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 462.2062 [M+H]⁺, (C₂₄H₂₅FN₇O₂) [M+H]⁺theoretical value: 462.2054;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.23 (s, 1H), 8.63 (s, 1H), 8.32 (s,1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.31 (s, 1H), 6.43 (s, 1H), 4.61 (s,1H), 3.92 (s, 3H), 1.98 (s, 1H), 1.79 (s, 1H), 1.74-1.26 (m, 8H).

Example 13:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-6-(1-methyl-1H-pyrrol-3-yl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in THF(20 mL) was added Pd(PPh₃)₂Cl₂ (191 mg, 0.27 mmol),(1-methylpyrrol-3-yl)boronic acid (627 mg, 2.73 mol) and Na₂CO₃ aqueoussolution (1 M, 5.45 mL, 5.45 mmol). The reaction mixture was heated to70° C. and stirred for 4 h under nitrogen protection. Then 50 mL ofwater was added to the mixture. The resulting mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with saturatedbrine (100 mL), dried over anhydrous Na₂SO₄ and filtered, then thefiltrate was concentrated in vacuo. The residue was purified by silicagel column chromatography (n-hexane/EtOAc (v/v)=5/1) to give the titlecompound as a white solid (484 mg, 78%).

MS (ESI, pos. ion) m/z: 228.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.48 (s, 1H), 7.25 (s, 1H), 6.70-6.58(m, 2H), 3.73 (s, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (466 mg, 2.54 mmol),2,4-dichloro-6-(1-methylpyrrol-3-yl)pyrimidine (484 mg, 2.12 mmol) inDMF (6 mL) was added potassium carbonate (879 mg, 6.36 mmol). Then themixture was stirred at room temperature overnight. Water (40 mL) wasadded to the mixture and the resulting mixture was extracted with EtOAc(40 mL×3). The combined organic layers were washed with saturated brine(100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=5/1) to give the title compound as a white solid (234 mg, 29%).

MS (ESI, pos. ion) m/z: 375.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.39 (s, 1H), 6.62 (s, 1H), 6.57 (s,1H), 6.44 (s, 1H), 5.32 (s, 2H), 4.24 (d, J=5.8 Hz, 1H), 3.74 (s, 3H),3.69 (s, 3H), 2.37 (d, J=4.8 Hz, 1H), 1.86 (d, J=2.5 Hz, 1H), 1.71-1.40(m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A microwave tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(647 mg, 0.78 mmol), (+/−)-trans-methyl3-((2-chloro-6-(1-methylpyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(243 mg, 0.65 mmol), potassium acetate (268 mg, 1.95 mmol), Pd(dppf)Cl₂(105 mg, 0.13 mmol), 1,4-dioxane (3 mL) and H₂O (0.2 mL). The resultingmixture was bubbled with nitrogen for 10 minutes and stirred at 110° C.with microwave heating for 2 h. The reaction mixture was filteredthrough a celite pad and the filter cake was washed with EtOAc (50 mL).The obtained filtrate was washed with saturated brine (50 mL), driedover anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a brown solid(330 mg, 81%).

MS (ESI, pos. ion) m/z: 629.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.70-8.61 (m, 2H), 8.31 (s, 1H), 8.10(d, J=8.2 Hz, 2H), 7.42 (s, 1H), 7.27 (s, 1H), 6.67 (s, 2H), 6.43 (s,1H), 5.32 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.43 (d, J=5.0 Hz, 1H),2.38 (s, 3H), 1.96 (s, 1H), 1.73 (s, 10H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(l-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(330 mg, 0.52 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added NaOH aqueoussolution (4 M, 1.30 mL, 5.20 mmol) and the resulting mixture was stirredovernight at 30° C. Water (10 mL) was added to the mixture and theresulting mixture was adjusted with HCl (1 M) to pH about 5.5. Then themixture was extracted with EtOAc (20 mL×3). The combined organic layerswere washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) togive the title compound as a yellow solid (42 mg, 17%).

MS (ESI, pos. ion) m/z: 461.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.2114 [M+H]⁺, (C₂₄H₂₃FN₅O₃) [M+H]⁺theoretical value: 461.2101;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.63 (s, 1H), 8.27 (s,2H), 7.51 (s, 1H), 7.28 (s, 1H), 6.81 (s, 1H), 6.55 (s, 1H), 6.41 (s,1H), 4.60 (s, 1H), 3.62 (s, 3H), 2.03-1.30 (m, 10H).

Example 14:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[4,5′-bipyrimidin]-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,6-dichloro-4,5′-bipyrimidine

To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) inacetonitrile (4 mL) was added Pd(dppf)Cl₂ (89 mg, 0.11 mmol),pyrimidin-5-ylboronic acid (67 mg, 0.55 mol), CsCO₃ (266 mg, 0.82 mmol)and H₂O (0.5 mL). The reaction mixture was heated to 95° C. undernitrogen protection and stirred for 5 h. Then 50 mL of water was addedto the mixture. The mixture was extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with saturated brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) togive the title compound as a red solid (44 mg, 36%).

MS (ESI, pos. ion) m/z: 228.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.41 (s, 3H), 7.76 (s, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-[4,5′-bipyrimidin]-6-yl)amino)bicycle[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (73 mg, 0.40 mmol),2,6-dichloro-4,5′-bipyrimidine (76 mg, 0.33 mmol) in DMF (2 mL) wasadded potassium carbonate (138 mg, 1.00 mmol). Then the mixture wasstirred at room temperature overnight. Water (40 mL) was added to themixture and the resulting mixture was extracted with EtOAc (40 mL×3).The combined organic layers were washed with saturated brine (50 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo to dry. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/1) to give the title compound as awhite solid (65 mg, 52%).

MS (ESI, pos. ion) m/z: 374.4[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.32 (s, 3H), 6.95 (s, 1H), 5.77 (s,1H), 4.36 (s, 1H), 3.77 (s, 3H), 2.41 (d, J=3.4 Hz, 1H), 1.88 (s, 1H),1.83-1.65 (m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[4,5′-bipyrimidin]-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A microwave tube was charged with5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(173 mg, 0.21 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-[4,5′-bipyrimidin]-6-yl)amino)bicycle[2.2.2]octane-2-carboxylate(65 mg, 0.17 mmol), potassium acetate (72 mg, 0.52 mmol), Pd(dppf)Cl₂(28 mg, 0.03 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The resultingsolution was bubbled with nitrogen for 10 minutes to remove the air andthen stirred at 110° C. for 2 h with microwave heating. The reactionmixture was filtered through a celite pad and the filter cake was washedwith EtOAc (50 mL). The filtrate was washed with saturated brine (50mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a brown solid(50 mg, 46%).

MS (ESI, pos. ion) m/z: 628.7 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.41 (s, 2H), 9.35 (s, 1H), 8.73 (s,1H), 8.35 (s, 1H), 8.15 (d, J=8.3 Hz, 2H), 5.37 (s, 1H), 3.76 (s, 3H),2.46 (s, 1H), 2.40 (s, 3H), 2.14 (s, 1H), 2.05-1.99 (m, 2H), 1.49-1.41(m, 8H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[4,5′-bipyrimidin]-6-yl)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-[4,5′-bipyrimidin]-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(50 mg, 0.08 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added NaOH aqueoussolution (4 M, 0.2 mL, 0.80 mmol) and the mixture was stirred overnightat 30° C. Water (10 mL) was added to the mixture and the mixture wasadjusted with HCl (1 M) to pH about 5.5. Then the mixture was extractedwith EtOAc (20 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to remove the solvent. The obtainedresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a yellow solid (20 mg, 55%).

MS (ESI, pos. ion) m/z: 460.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 460.1905 [M+H]⁺, (C₂₄H₂₃FN₇O₂)[M+H]⁺theoretical value: 460.1897;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.36 (s, 1H), 9.60 (s, 1H), 9.44 (s,1H), 9.31 (s, 1H), 8.60 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.78 (s,1H), 6.88 (s, 1H), 4.69 (s, 1H), 2.01 (s, 2H), 1.88-1.32 (m, 8H).

Example 15:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

Step 1:(+/−)-cis-3-tert-butoxycarbonylamino-1-benzyloxyecarbonylaminocyclohexane

To a solution of(+/−)-cis-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (5 g,20.6 mmol) in toluene (60 mL) were added triethylamine (4.6 mL, 33.0mmol) and diphenylphosphoryl azide (5.32 mL, 24.7 mmol), and the mixturewas stirred for 3 h at rt. Then benzyl alcohol (4.27 mL, 41.1 mmol) wasadded, and the resulting mixture was stirred at 100° C. overnight undernitrogen protection. The reaction mixture was diluted with ethyl acetate(60 mL), and the resulting mixture was washed with saturated brine (60mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=5/1) to give the title compound as darkyellow oil (7.16 g, 100%).

Step 2: (+/−)-cis-N-tert-butoxycarbonyl-1,3-cyclohexanediamine

A solution of(+/−)-cis-3-tert-butoxycarbonylamino-1-benzyloxycarbonylaminocyclohexane (7.2 g, 21 mmol) in methanol (100 mL) was placed in anautoclave, and to the solution was added Pd/C (10% Pd, 2 g). Theresulting mixture was stirred at rt overnight in hydrogen atmosphereunder a pressure of 2 MPa. The reaction mixture was filtered through acelite pad to remove the catalyst, then the filter cake was washed witha mixture of methanol (200 mL) and ethyl acetate (200 mL). The filtratewas concentrated in vacuo to dry and the residue was purified bysilica-gel column chromatography (DCM/MeOH (v/v)=20/1-10/1) to give thetitle compound as colourless oil (1.65 g, 37%).

MS (ESI, pos. ion) m/z: 215.1 [M+H]⁺.

Step 3: 2,4-dichloro-6-phenylpyrimidine

To a solution of 2,4,6-trichloropyrimidine (0.29 mL, 2.5 mmol) intetrahydrofuran (5 mL) were added palladium acetate (8 mg, 0.035 mmol),triphenylphosphine (18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6mmol) and aqueous sodium carbonate solution (1 M, 3.3 mL, 3.3 mmol). Themixture was stirred at 60° C. for 6 h, then cooled to rt andconcentrated to remove the organic solvent. To the residue was added H₂O(10 mL), and the mixture was extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with saturated brine (30 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dry and the residue was purified by silica gelcolumn chromatography (PE) to give the title compound as a white solid(0.225 g, 61%).

MS (ESI, pos. ion) m/z: 224.95 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H),7.63-7.50 (m, 3H).

Step 4: (+/−)-cis-tert-butyl(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl) carbamate

To a solution of 2,4-dichloro-6-phenylpyrimidine (727 mg, 3.23 mmol) and(+/−)-cis-N-tert-butoxycarbonyl-1,3-cyclohexanediamine (630 mg, 2.94mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate(1.22 g, 8.82 mmol). The mixture was stirred at rt overnight. To thereaction mixture was added water (50 mL) and the resulting mixture wasextracted with EtOAc (40 mL×3). The combined organic layers were washedwith saturated brine (100 mL), dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a white solid (516 mg, 43%).

MS-ESI: (ESI, pos. ion) m/z: 403.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02-7.93 (m, 2H), 7.53-7.44 (m, 3H),6.59 (s, 1H), 4.45 (s, 1H), 3.60 (s, 1H), 2.43 (d, J=11.8 Hz, 1H), 2.10(d, J=14.5 Hz, 2H), 1.89 (d, J=14.0 Hz, 1H), 1.63 (s, 4H), 1.57-1.43 (m,11H).

Step 5: N¹-(2-chloro-6-phenylpyrimidin-4-yl)cyclohexane-1,3-diamine

To a solution of hydrochloric acid in 1,4-dioxane (1.1 mL, 5.5 mmol, 5mol/L) was added (+/−)-cis-tert-butyl(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)carbamate (220 mg,0.55 mmol), and the mixture was stirred at rt overnight. The reactionmixture was concentrated in vacuo to remove the solvent and to theresidue was added an appropriate amount of water. The resulting mixturewas adjusted with saturated aqueous sodium carbonate to pH 9. Themixture was extracted with ethyl acetate (20 mL×3), and the combinedorganic layers were washed with saturated brine (50 mL), dried overanhydrous sodium sulfate, then filtered. The filtrate was concentratedin vacuo to dryness to give the title compound as a white solid (144 mg,87%).

MS (ESI, pos. ion) m/z: 303.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.99-7.89 (m, 2H), 7.58-7.41 (m, 3H),6.57 (s, 1H), 5.74 (s, 1H), 2.25-2.14 (m, 1H), 2.00 (d, J=13.2 Hz, 1H),1.88 (d, J=9.8 Hz, 2H), 1.58-1.37 (m, 2H), 1.30-1.12 (m, 4H).

Step 6:(+/−)-cis-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a solution ofN¹-(2-chloro-6-phenylpyrimidin-4-yl)cyclohexane-1,3-diamine (65 mg, 0.21mmol) in a mixed solvent of tetrahydrofuran (4 mL) and dimethylsulfoxide (1 mL) were added N,N-diisopropylethylamine (0.11 mL, 0.7mmol) and 1H-1,2,3-triazole-4-carboxylic acid (48 mg, 0.42 mmol). Themixture was stirred at rt for 10 min, then HATU (163 mg, 0.43 mmol) wasadded, and the resulting mixture was stirred at rt for 3 hours. To thereaction mixture was added water (10 mL), and the resulting mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with saturated brine (30 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to give the titlecompound as a colorless solid (85 mg, 100%).

MS (ESI, pos. ion) m/z: 398.5 [M+H]⁺.

Step 7:(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(652 mg, 0.55 mmol, 50%),(+/−)-cis-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide(85 mg, 0.21 mmol), potassium carbonate (88 mg, 0.64 mmol), Pd(dppf)Cl₂(34 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (139 mg, 100%).

MS (ESI, pos. ion) m/z: 652.2[M+H]⁺.

Step 8:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide(192 mg, 0.29 mmol) in methanol (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.6 mL, 2.9 mmol). The mixture was stirredat 30° C. overnight. The reaction mixture was concentrated in vacuo todry and to the residue was added water (10 mL). The resulting mixturewas extracted with ethyl acetate (20 mL×3), and the combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a white solid (25 mg, 60%).

MS (ESI, pos. ion) m/z: 498.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 498.2169 [M+H]⁺, (C₂₆H₂₅FN₉O)[M+H]⁺theoretical value: 498.2166;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.29 (s, 1H), 8.58 (s, 1H), 8.41 (s,2H), 8.29 (s, 1H), 8.11 (s, 2H), 7.58-7.48 (m, 3H), 7.42 (s, 1H), 6.76(s, 1H), 4.15 (s, 1H), 4.04 (s, 1H), 2.30-1.79 (m, 6H).

Example 16:(+/−)-trans-3-((6-(benzofuran-2-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 4-(benzofuran-2-yl)-2,6-dichloropyrimidine

To a solution of 2,4,6-trichloropyrimidine (50 mg, 0.27 mmol) in a mixedsolvent of toluene (3 mL) and ethanol (1 mL) were addedtetrakis(triphenylphosphine)palladium (31 mg, 0.03 mmol),benzofuran-2-ylboronic acid (44 mg, 0.28 mmol) and aqueous sodiumcarbonate solution (1 M, 0.82 mL, 0.82 mmol). The mixture was stirred at85° C. for 4 h under nitrogen protection. To the reaction mixture wasadded water (10 mL), and the resulting mixture was extracted with ethylacetate (10 mL×3). The combined organic layers were washed withsaturated brine (30 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE) to give the titlecompound as a white solid (26 mg, 36%).

MS (ESI, pos. ion) m/z: 265.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.80 (d, J=4.1 Hz, 2H), 7.73 (d, J=7.8Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.5Hz, 1H).

Step 2: (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-chloropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (628 mg,3.43 mmol) and 4-(benzofuran-2-yl)-2,6-dichloropyrimidine (758 mg, 2.86mmol) were dissolved in DMF (5 mL), then potassium carbonate (1.19 g,8.58 mmol) was added. The mixture was stirred at rt overnight. To thereaction mixture was added water (40 mL), and the resulting mixture wasextracted with ethyl acetate (40 mL×3). The combined organic layers werewashed with saturated brine (100 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a white solid (553 mg, 47%).

MS (ESI, pos. ion) m/z: 412.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.68 (d, J=7.5 Hz, 1H), 7.62-7.54 (m,2H), 7.40 (dd, J=9.4, 5.9 Hz, 2H), 6.91 (s, 1H), 5.57 (s, 1H), 4.36 (s,1H), 3.78 (s, 3H), 2.40 (d, J=5.2 Hz, 1H), 2.34 (d, J=3.7 Hz, 1H), 1.90(d, J=2.6 Hz, 1H), 1.85-1.69 (m, 8H).

Step 3: (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(455 mg, 0.44 mmol, 50%), (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-chloropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(166 mg, 0.40 mmol), potassium carbonate (165 mg, 1.20 mmol),Pd(dppf)Cl₂ (65 mg, 0.08 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The air in the mixture was removed by bubbling with nitrogen for 10 min,then the mixture in the microwave tube was stirred at 110° C. withmicrowave heating for 2 hours. The mixture was filtered through a celitepad, and the filter cake was washed with ethyl acetate (50 mL). Thefiltrate was washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(57 mg, 35%).

MS (ESI, pos. ion) m/z: 666.3[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.77-8.67 (m, 2H), 8.35 (d, J=1.7 Hz,1H), 8.15 (d, J=8.3 Hz, 2H), 7.74 (d, J=7.7 Hz, 1H), 7.65 (s, 1H), 7.59(d, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.32 (t, J=8.2 Hz, 3H), 6.89(s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.77 (s, 3H), 2.47 (d, J=5.5 Hz,1H), 2.40 (s, 3H), 2.12 (s, 1H), 2.01 (s, 1H), 1.97-1.62 (m, 8H).

Step 4:(+/−)-trans-3-((6-(benzofuran-2-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(57 mg, 0.09 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added aqueous sodiumhydroxide solution (4 M, 0.23 mL, 0.90 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were dried over anhydrous sodium sulfate,then filtered. The filtrate was concentrated in vacuo to remove thesolvent and the residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a yellow solid (22mg, 52%).

MS (ESI, pos. ion) m/z: 498.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 498.1931 [M+H]⁺, (C₂₈H₂₅FN₅O₃)[M+H]⁺theoretical value: 498.1941;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.33 (s, 1H), 8.60 (s, 1H), 8.43 (s,1H), 8.38 (t, J=9.5 Hz, 4H), 8.30 (s, 1H), 7.66 (s, 1H), 6.88 (s, 1H),4.71 (s, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 1.79-1.41 (m, 8H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 185.05, 162.79, 162.67, 155.32,155.14, 154.87, 152.39, 146.48, 131.92, 131.87, 131.66, 128.61, 126.28,123.98, 122.63, 119.01, 111.88, 106.59, 67.49, 50.06, 29.49, 28.75,28.45, 25.60, 24.20, 21.38, 19.43.

Example 17:(+/−)-trans-3-((6-(benzo[b]thiophen-2-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 4-(benzo[b]thiophen-2-yl)-2,6-dichloropyrimidine

To a solution of 2,4,6-trichloropyrimidine (50 mg, 0.27 mmol) in a mixedsolvent of toluene (3 mL) and ethanol (1 mL) were addedtetrakis(triphenylphosphine)palladium (31 mg, 0.03 mmol),benzo[b]thiophen-2-ylboronic acid (49 mg, 0.28 mmol) and aqueous sodiumcarbonate solution (1 M, 0.82 mL, 0.82 mmol). The mixture was stirred at85° C. for 4 h under nitrogen protection. To the reaction mixture wasadded water (10 mL), and the resulting mixture was extracted with ethylacetate (10 mL×3). The combined organic layers were washed withsaturated brine (30 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE) to give the titlecompound as a white solid (24 mg, 31%).

MS (ESI, pos. ion) m/z: 280.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.17 (s, 1H), 7.91 (t, J=6.4 Hz, 2H),7.64 (s, 1H), 7.51-7.43 (m, 2H).

Step 2: (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-chloropyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (409 mg,2.23 mmol) and 4-(benzo[b]thiophen-2-yl)-2,6-dichloropyrimidine (523 mg,1.86 mmol) were dissolved in DMF (5 mL), then potassium carbonate (771mg, 5.58 mmol) was added. The mixture was stirred at rt overnight. Tothe reaction mixture was added water (40 mL), and the resulting mixturewas extracted with ethyl acetate (40 mL×3). The combined organic layerswere washed with saturated brine (50 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a white solid (357 mg, 45%).

MS (ESI, pos. ion) m/z: 428.6 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (s, 1H), 7.91-7.81 (m, 2H),7.43-7.36 (m, 2H), 6.80 (s, 1H), 5.50 (s, 1H), 4.35 (s, 1H), 3.78 (s,3H), 2.41 (d, J=4.9 Hz, 1H), 2.10 (s, 1H), 1.90 (d, J=2.6 Hz, 1H),1.84-1.63 (m, 6H), 1.58-1.43 (m, 2H).

Step 3: (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(233 mg, 0.28 mmol), (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-chloropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.23 mmol), potassium carbonate (96 mg, 0.70 mmol), Pd(dppf)Cl₂(38 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 110° C. with microwaveheating for 2 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrated waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (147 mg, 92%).

MS (ESI, pos. ion) m/z: 682.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.79 (dd, J=9.0, 2.8 Hz, 1H), 8.71 (s,1H), 8.35 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 2H), 7.99 (s, 1H),7.96-7.92 (m, 1H), 7.90-7.85 (m, 1H), 7.44-7.39 (m, 2H), 7.30 (d, J=8.3Hz, 2H), 6.80 (s, 1H), 5.28 (s, 1H), 4.55 (s, 1H), 3.77 (s, 3H), 2.47(d, J=5.2 Hz, 1H), 2.40 (s, 3H), 2.12 (s, 1H), 1.99 (s, 1H), 1.92-1.63(m, 8H).

Step 4:(+/−)-trans-3-((6-(benzo[b]thiophen-2-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(147 mg, 0.22 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added aqueous sodiumhydroxide solution (4 M, 0.55 mL, 2.20 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine (50 mL) anddried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give thetitle compound as a yellow solid (54 mg, 49%).

MS (ESI, pos. ion) m/z: 514.2 [M+1]⁺;

HRMS (ESI, pos. ion) m/z: 514.1710 [M+H]⁺, (C₂₄H₂₅FN₇O₂)[M+H]⁺theoretical value: 514.1713;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.32 (s, 1H), 8.69 (s, 1H), 8.34 (s,1H), 8.32 (s, 1H), 8.11 (s, 1H), 8.09-8.05 (m, 1H), 7.97 (s, 1H), 7.60(s, 1H), 7.43 (dd, J=5.8, 3.1 Hz, 2H), 6.85 (s, 1H), 4.62 (s, 1H), 1.99(s, 2H), 1.84-1.40 (m, 8H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 175.97, 162.74, 162.41, 157.35,154.96, 146.50, 144.31, 140.47, 140.21, 131.98, 131.69, 125.96, 125.21,124.98, 123.21, 119.04, 118.97, 114.52, 50.72, 28.75, 28.56, 26.01,25.59, 24.22, 21.37, 19.45.

Example 18:(+/−)-trans-3-((6-(dibenzo[b,d]furan-4-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-6-(dibenzo[b,d]furan-4-yl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in1,2-dimethoxyethane (32 mL) were addedtetrakis(triphenylphosphine)palladium (316 mg, 0.27 mmol),dibenzo[b,d]furan-4-ylboronic acid (583 mg, 2.75 mmol) and aqueoussodium carbonate solution (1 M, 8.18 mL, 8.18 mmol). The mixture wasstirred at 80° C. for 2 h. To the reaction mixture was added water (30mL), and the resulting mixture was extracted with ethyl acetate (30mL×3). The combined organic layers were washed with saturated brine (30mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE) to give the title compound as a white solid (550 mg,31%).

MS (ESI, pos. ion) m/z: 315.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.58 (s, 1H), 8.56-8.51 (m, 1H),8.19-8.15 (m, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.57(dt, J=15.4, 4.4 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(dibenzo[b,d]furan-4-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (418 mg,2.28 mmol) and 2,4-dichloro-6-(dibenzo[b,d]furan-4-yl)pyrimidine (600mg, 1.90 mmol) were dissolved in DMF (6 mL), then potassium carbonate(789 mg, 5.71 mmol) was added. The mixture was stirred at rt overnight.To the reaction mixture was added water (40 mL), and the resultingmixture was extracted with ethyl acetate (40 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a white solid (586 mg, 67%).

MS (ESI, pos. ion) m/z: 462.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.45 (d, J=7.6 Hz, 1H), 8.07 (d, J=7.4Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.55-7.38 (m, 5H), 5.54 (s, 1H), 4.46(s, 1H), 3.72 (s, 3H), 2.46 (d, J=5.3 Hz, 1H), 2.10 (s, 1H), 2.03 (s,1H), 1.94-1.67 (m, 8H).

Step 3: (+/−)-trans-methyl3-((6-(dibenzo[b,d]furan-4-yl)-2-(5-fluoro-l-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(237 mg, 0.29 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-(dibenzo[b,d]furan-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(110 mg, 0.24 mmol), potassium carbonate (98 mg, 0.71 mmol), Pd(dppf)Cl₂(38 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 110° C. with microwaveheating for 2 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrated waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to dry and theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=5/1) to give the title compound as a yellow solid (91 mg, 53%).

MS (ESI, pos. ion) m/z: 716.3[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.81 (dd, J=8.9, 2.7 Hz, 1H), 8.77 (s,1H), 8.53 (d, J=7.8 Hz, 1H), 8.35 (s, 1H), 8.15 (d, J=8.1 Hz, 2H), 8.11(d, J=7.7 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55(dd, J=14.7, 9.1 Hz, 2H), 7.44 (d, J=7.5 Hz, 1H), 7.39 (d, J=4.3 Hz,2H), 7.31 (s, 1H), 5.28 (s, 1H), 4.73 (d, J=4.7 Hz, 1H), 3.73 (s, 3H),2.52 (d, J=5.7 Hz, 1H), 2.40 (s, 3H), 2.13 (s, 2H), 1.74 (m, 8H).

Step 4:(+/−)-trans-3-((6-(dibenzo[b,d]furan-4-yl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-(dibenzo[b,d]furan-4-yl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(91 mg, 0.13 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added aqueous sodiumhydroxide solution (4 M, 0.33 mL, 1.30 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine (50 mL) anddried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as ayellow solid (45 mg, 65%).

MS (ESI, pos. ion) m/z: 548.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 548.2118 [M+H]⁺, (C₃₂H₂₆FN₅O₃)[M+H]⁺theoretical value: 548.2098;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.30 (s, 1H), 8.71 (d, J=7.6 Hz,1H), 8.52 (d, J=7.0 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J=7.2 Hz, 2H), 8.25(d, J=7.6 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.62 (t, J=7.6Hz, 2H), 7.48 (t, J=7.5 Hz, 1H), 7.43 (s, 1H), 4.71 (s, 1H), 2.58 (s,1H), 1.93-1.37 (m, 10H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.04, 172.49, 163.00, 162.42,156.90, 156.75, 155.86, 155.30, 153.79, 146.50, 131.80, 131.72, 131.61,128.44, 127.44, 125.15, 123.96, 123.92, 123.72, 123.22, 122.94, 121.79,119.12, 119.06, 115.75, 115.11, 112.07, 102.42, 67.48, 50.65, 49.82,29.49, 28.83, 28.53, 26.07, 25.59, 24.25, 21.52, 21.45, 19.52.

Example 19:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

Step 1:N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

To a solution ofN¹-(2-chloro-6-phenylpyrimidin-4-yl)cyclohexane-1,3-diamine (75 mg, 0.25mmol) in tetrahydrofuran (4 mL) was added N,N-diisopropylethylamine(0.12 mL, 0.74 mmol) and pyrrolidine-1-carbonyl chloride (49 mg, 0.37mmol). The mixture was stirred at rt overnight. To the reaction mixturewas added water (10 mL), and the resulting mixture was extracted withethyl acetate (10 mL×3). The combined organic layers were washed withsaturated brine (30 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness to give thetitle compound as a colorless solid (99 mg, 100%).

MS (ESI, pos. ion) m/z: 400.3[M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 7.91 (s, 2H), 7.49 (d, J=2.1 Hz, 3H),6.75 (s, 1H), 1.96-1.85 (m, 5H), 1.42 (s, 1H), 1.25 (m, 8H).

Step 2:(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(249 mg, 0.30 mmol, 50%),N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide(100 mg, 0.25 mmol), potassium carbonate (103 mg, 0.75 mmol),Pd(dppf)Cl₂ (40 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The mixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (83 mg, 51%).

MS (ESI, pos. ion) m/z: 654.3[M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.66 (s, 1H), 8.29 (s, 1H), 8.09 (t,J=7.5 Hz, 4H), 7.52 (d, J=7.5 Hz, 4H), 7.40 (d, J=8.2 Hz, 2H), 6.77 (s,1H), 5.88 (d, J=7.9 Hz, 1H), 4.59 (s, 2H), 3.80 (s, 1H), 2.39 (s, 3H),1.85-1.92 (m, 6H), 1.34 (m, 8H).

Step 3:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide

To a solution of(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide(83 mg, 0.13 mmol) in methanol (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.26 mL, 1.3 mmol). The mixture was stirredat 30° C. overnight. The reaction mixture was concentrated in vacuo todry and to the residue was added water (10 mL). The resulting mixturewas extracted with ethyl acetate (20 mL×3), and the combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate, then filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (32mg, 50%).

MS (ESI, pos. ion) m/z: 500.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 500.2568 [M+H]⁺, (C₂₈H₃₁FN₇O)[M+H]⁺theoretical value: 500.2574;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 8.58 (s, 1H), 8.39 (s,1H), 8.29 (s, 1H), 8.11 (s, 2H), 7.55-7.50 (m, 3H), 7.36 (s, 1H), 6.76(s, 1H), 5.84 (d, J=7.9 Hz, 1H), 4.11 (s, 1H), 3.66 (d, J=7.8 Hz, 1H),3.19 (d, J=6.4 Hz, 4H), 2.16 (s, 2H), 1.80 (s, 6H), 1.53-1.24 (m, 4H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 162.78, 162.43, 156.85, 156.37,155.26, 146.48, 138.46, 131.76, 131.56, 130.28, 129.19, 126.77, 119.08,119.03, 115.08, 56.50, 49.14, 48.61, 45.76, 33.01, 32.36, 29.43, 25.47,25.42, 23.50, 22.54, 19.01.

Example 20:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(furan-3-yl)pyrimidine

To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in1,2-dimethoxyethane (32 mL) were addedtetrakis(triphenylphosphine)palladium (317 mg, 0.27 mmol),3-furylboronic acid (308 mg, 2.75 mmol) and aqueous sodium carbonatesolution (1 M, 8.18 mL, 8.18 mmol). The mixture was stirred at 80° C.for 1 h. To the reaction mixture was added water (30 mL), and theresulting mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layers were washed with saturated brine (60 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dry and the residue was purified by silica gelcolumn chromatography (PE) to give the title compound as a white solid(317 mg, 31%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.26 (s, 1H), 7.57 (s, 1H), 7.36 (s,1H), 6.89 (s, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(furan-3-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (324 mg,1.77 mmol) and 2,4-dichloro-6-(furan-3-yl)pyrimidine (317 mg, 1.47 mmol)were dissolved in DMF (6 mL), then potassium carbonate (611 mg, 4.42mmol) was added. The mixture was stirred at rt overnight. To thereaction mixture was added water (40 mL), and the resulting mixture wasextracted with ethyl acetate (40 mL×3). The combined organic layers werewashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) togive the title compound as a white solid (353 mg, 66%).

MS (ESI, pos. ion) m/z: 362.1 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(290 mg, 0.35 mmol, 50%), (+/−)-trans-methyl3-((2-chloro-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(105 mg, 0.29 mmol), potassium carbonate (120 mg, 0.85 mmol),Pd(dppf)Cl₂ (47 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The air in the mixture was removed by bubbling with nitrogen for 10 min,then the mixture in the microwave tube was stirred at 110° C. withmicrowave heating for 2 hours. The mixture was filtered through a celitepad, and the filter cake was washed with ethyl acetate (50 mL). Thefiltrate was washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo todry and the residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(179 mg, 100%).

MS (ESI, pos. ion) m/z: 616.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66 (s, 1H), 8.63 (dd, J=8.9, 2.7 Hz,1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.55 (s, 1H),7.39 (d, J=4.6 Hz, 2H), 7.30 (s, 1H), 6.91 (s, 1H), 5.21 (s, 1H), 4.72(s, 1H), 3.74 (s, 3H), 2.45-2.42 (m, 1H), 2.39 (s, 3H), 2.10 (s, 1H),1.96 (s, 1H), 1.81 (m, 8H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(180 mg, 0.29 mmol) in THF/MeOH (v/v=1/1, 4 mL) was added aqueous sodiumhydroxide solution (4 M, 0.73 mL, 2.90 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine, dried overanhydrous sodium sulfate, then filtered. The filtrate was concentratedin vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as ayellow solid (62 mg, 47%).

MS (ESI, pos. ion) m/z: 448.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 448.1785 [M+H]⁺, (C₂₄H₂₃FN₇O₃)[M+H]⁺theoretical value: 448.1784;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.25 (s, 1H), 8.62 (s, 1H), 8.41 (s,1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 6.98 (s,1H), 6.48 (s, 1H), 4.63 (s, 1H), 3.17 (s, 1H), 1.99 (s, 2H), 1.88-1.44(m, 8H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 175.99, 172.43, 162.82, 162.39,157.27, 154.88, 146.46, 144.88, 143.19, 131.75, 131.60, 131.46, 126.56,119.05, 118.97, 116.07, 114.90, 108.96, 56.50, 50.48, 49.74, 49.05,28.78, 28.60, 25.99, 24.13, 21.50, 21.40, 19.41.

Example 21:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

Step 1:2-amino-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a solution ofN¹-(2-chloro-6-phenylpyrimidin-4-yl)cyclohexane-1,3-diamine (63 mg, 0.21mmol) in a mixed solvent of tetrahydrofuran (4 mL) and dimethylsulfoxide (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.62mmol) and 2-aminothiazole-4-carboxylic acid (59 mg, 0.42 mmol). Themixture was stirred at rt overnight. To the reaction mixture was addedwater (10 mL), and the resulting mixture was extracted with ethylacetate (10 mL×3). The combined organic layers were washed withsaturated brine (10 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to give the titlecompound as a white solid (89 mg, 100%).

MS (ESI, pos. ion) m/z: 429.2[M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 7.92 (s, 2H), 7.49 (s, 3H), 7.26 (s,1H), 6.77 (s, 1H), 4.59 (s, 1H), 2.68 (s, 1H), 2.32 (d, J=11.1 Hz, 1H),2.11-1.90 (m, 4H), 1.59 (d, J=13.1 Hz, 1H).

Step 2:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(209 mg, 0.25 mmol, 50%),(+/−)-cis-2-amino-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide(90 mg, 0.21 mmol), potassium phosphate (133 mg, 0.63 mmol), Pd₂(dba)₃(20 mg, 0.02 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 120° C. under microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (43 mg, 30%).

Step 3:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a solution of(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide(43 mg, 0.06 mmol) in methanol (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.12 mL, 0.6 mmol). The mixture was stirredat 30° C. overnight. The reaction mixture was concentrated in vacuo andto the residue was added water (10 mL). The resulting mixture wasextracted with ethyl acetate (20 mL×3), and the combined organic layerswere washed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, then filtered. The filtrate was concentrated in vacuo to removethe solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as awhite solid (32 mg, 50%).

MS (ESI, pos. ion) m/z: 529.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 529.1940 [M+H]⁺, (C₂₇H₂₆FN₈OS)[M+H]⁺theoretical value: 529.1934;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 8.60 (s, 1H), 8.40 (s,1H), 8.29 (s, 1H), 8.11 (s, 2H), 7.58-7.48 (m, 4H), 7.38 (s, 1H), 7.18(s, 1H), 7.08 (s, 2H), 6.77 (s, 1H), 4.12 (s, 1H), 3.94 (s, 1H), 1.86(s, 2H), 1.44 (m, 6H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 168.62, 162.43, 160.44, 156.86,155.27, 146.48, 146.21, 138.44, 131.77, 131.58, 130.31, 130.12, 129.20,126.80, 119.07, 119.02, 115.10, 111.69, 48.86, 32.08, 31.75, 30.86,29.47, 29.15, 22.55, 14.42.

Example 22:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

Step 1:(+/−)-cis-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a solution ofN¹-(2-chloro-6-phenylpyrimidin-4-yl)cyclohexane-1,3-diamine (221 mg,0.73 mmol) in a mixed solvent of tetrahydrofuran (4 mL) and dimethylsulfoxide (1 mL) were added N,N-diisopropylethylamine (0.11 mL, 0.7mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (184 mg, 1.46 mmol).The mixture was stirred at rt for 10 min, then HATU (555 mg, 1.46 mmol)was added. The resulting mixture was stirred at rt for 3 h. To thereaction mixture was added water (10 mL), and the resulting mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with saturated brine (30 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to give the titlecompound as a colorless solid (180 mg, 60%).

MS (ESI, pos. ion) m/z: 411.2 [M+H]⁺.

Step 2:(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(162 mg, 0.23 mmol, 60%),(+/−)-cis-N-(3-((2-chloro-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide(80 mg, 0.19 mmol), potassium carbonate (80 mg, 0.58 mmol), Pd(dppf)Cl₂(31 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to dry and theresidue was purified by silica gel column chromatography (n-hexane/EtOAc(v/v)=5/1) to give the title compound as a yellow solid (20 mg, 15%).

MS (ESI, pos. ion) m/z: 665.2[M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.73 (d, J=3.2 Hz, 1H), 8.68 (s, 1H),8.40 (d, J=8.7 Hz, 1H), 8.29 (s, 1H), 8.10 (d, J=8.2 Hz, 4H), 7.63 (s,2H), 7.53 (d, J=7.5 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 6.79 (s, 1H), 4.10(s, 1H), 3.77 (s, 3H), 2.45 (s, 1H), 2.39 (s, 3H), 2.27-2.17 (m, 2H),2.10-1.97 (m, 4H), 1.62 (s, 2H).

Step 3:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a solution of(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide(20 mg, 0.03 mmol) in methanol (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.06 mL, 0.3 mmol). The mixture was stirredat 30° C. overnight. The reaction mixture was concentrated in vacuo andto the residue was added water (10 mL). The resulting mixture wasextracted with ethyl acetate (20 mL×3), and the combined organic layerswere washed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, then filtered. The filtrate was concentrated in vacuo to removethe solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as awhite solid (10 mg, 65%).

HRMS (ESI, pos. ion) m/z: 511.2385 [M+H]⁺, (C₂₈H₂₈FN₅O)[M+H]⁺theoretical value: 511.2370;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.59 (s, 1H), 8.40 (s,1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.64 (s, 1H),7.61 (s, 1H), 7.57-7.50 (m, 2H), 7.37 (s, 1H), 6.75 (s, 1H), 4.14 (s,1H), 3.68 (s, 3H), 2.20 (s, 2H), 1.84 (s, 2H), 1.55-1.33 (m, 4H).

Example 23:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(thiophen-2-yl)pyrimidine

To a solution of thiophene (500 mg, 5.94 mmol) in anhydroustetrahydrofuran (20 mL) was added n-butyllithium (2.4 mL, 6.0 mmol, 2.5mol/L) at −15° C., and the mixture was stirred for 1 h at −15° C. Thento the mixture was added ZnCl-TMEDA (495 mg, 1.96 mmol), and theresulting mixture was stirred for 1 h. Then palladium dichloride (105mg, 0.59 mmol), triphenylphosphine (658 mg, 1.19 mmol) and2,4,6-trichloropyrimidine (1.09 g, 5.94 mmol) were added to the mixturein turn. The resulting mixture was heated to 55° C. under nitrogenprotection, and then stirred at this temperature overnight. To thereaction mixture was added water (50 mL), and the resulting mixture wasextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with saturated brine (100 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE) to givethe title compound as a white solid (616 mg, 45%).

MS (ESI, pos. ion) m/z: 230.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.86 (d, J=3.7 Hz, 1H), 7.66 (d, J=4.9Hz, 1H), 7.51 (s, 1H), 7.24-7.17 (m, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (586 mg,3.20 mmol) and 2,4-dichloro-6-(thiophen-2-yl)pyrimidine (616 mg, 2.67mmol) were dissolved in DMF (6 mL), then potassium carbonate (1.11 g,8.00 mmol) was added. The mixture was stirred at rt overnight. To thereaction mixture was added water (40 mL), and the resulting mixture wasextracted with ethyl acetate (40 mL×3). The combined organic layers werewashed with saturated brine (100 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=5/1) to give the title compound as a white solid (180 mg, 18%).

MS (ESI, pos. ion) m/z: 378.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.74 (d, J=3.1 Hz, 1H), 7.50 (d, J=4.9Hz, 1H), 7.17-7.10 (m, 1H), 6.68 (s, 1H), 5.47 (s, 1H), 4.30 (s, 1H),3.76 (s, 3H), 2.39 (d, J=4.6 Hz, 1H), 2.08 (s, 1H), 1.87 (d, J=2.5 Hz,1H), 1.82-1.65 (m, 8H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(176 mg, 0.25 mmol, 60%), methyl3-((2-chloro-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (80 mg, 0.21 mmol), potassiumcarbonate (87 mg, 0.64 mmol), Pd(dppf)Cl₂ (34 mg, 0.04 mmol),1,4-dioxane (3 mL) and water (0.2 mL). The air in the mixture wasremoved by bubbling with nitrogen for 10 min, then the mixture in themicrowave tube was stirred at 110° C. with microwave heating for 2hours. The mixture was filtered through a celite pad, and the filtercake was washed with ethyl acetate (50 mL). The filtrate was washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (40 mg, 30%).

MS (ESI, pos. ion) m/z: 632.3[M+H]⁺.

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(40 mg, 0.06 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added aqueous sodiumhydroxide solution (4 M, 0.15 mL, 0.60 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give thetitle compound as a yellow solid (20 mg, 68%).

MS (ESI, pos. ion) m/z: 464.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 464.1526 [M+H]⁺, (C₂₄H₂₃FN₅O₂S)[M+H]⁺theoretical value: 464.1556;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.67 (s, 1H), 8.29 (s,2H), 7.73 (d, J=4.8 Hz, 2H), 7.48 (s, 1H), 7.26-7.17 (m, 1H), 6.68 (s,1H), 4.58 (s, 1H), 1.98-1.91 (m, 2H), 1.84-1.38 (m, 8H).

Example 24(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-(5-nitrofuran-2-yl)pyrimidine

To concentrated sulfuric acid (10 mL) was added2,4-dichloro-6-(furan-2-yl) pyrimidine (2.15 g, 10.00 mmol). The mixturewas placed in an ice-bath and stirred, then concentrated nitric acid(0.85 mL, 12 mmol) was added dropwise slowly to the mixture. Then theresulting mixture was warmed to room temperature and continued stirred.The reaction was stopped, and the reaction mixture was added dropwiseslowly to ice-water (50 mL) to quench the reaction. The resultingmixture was extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with saturated brine (80 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as yellow power (1.02 g, 39%).

MS (ESI, pos. ion) m/z: 260.10 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.81 (s, 1H), 7.57 (d, J=3.8 Hz, 1H),7.48 (d, J=3.8 Hz, 1H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

A suspension of 2,4-dichloro-6-(5-nitrofuran-2-yl)pyrimidine (300 mg,1.15 mmol), (+/−)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate(280 mg, 1.38 mmol) and K₂CO₃ (320 mg, 2.31 mmol) in DMF (10 mL) wasstirred at rt overnight. The reaction was quenched with water (100 mL),and the resulting mixture was extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with saturated brine (80 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=5/1) to give the title compound as awhite solid (344 mg, 73%).

MS (ESI, pos. ion) m/z: 407.20 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.42 (d, J=3.7 Hz, 1H), 7.36 (d, J=3.2Hz, 1H), 6.89 (s, 1H), 4.33 (s, 1H), 3.80 (s, 3H), 2.40 (d, J=4.4 Hz,1H), 2.06 (s, 1H), 1.87 (s, 1H), 1.81-1.56 (m, 9H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(170 mg, 0.41 mmol), K₂CO₃ (154 mg, 1.11 mmol), PdCl₂(dppf) (30 mg, 0.04mmol) and (+/−)-trans-methyl 3-((2-chloro-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (150 mg, 0.37mmol). Then H₂O (1 mL) was added to the mixture, and the air in themixture was removed by bubbling with nitrogen for 10 min. The mixturewas sealed in a tube, and stirred for 3 h at 115° C. The mixture wasfiltered to remove solid impurities, and the filtrate was concentratedto remove the solvent. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1-5/1) to give the title compound as awhite solid (126 mg, 52%).

MS (ESI, pos. ion) m/z: 661.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.70 (s, 1H), 8.59 (dd, J=8.8, 2.7 Hz,1H), 8.34 (d, J=1.7 Hz, 1H), 8.15 (d, J=8.2 Hz, 2H), 7.49 (d, J=3.8 Hz,1H), 7.41 (d, J=3.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 6.85 (s, 1H), 5.37(s, 1H), 3.78 (s, 3H), 2.44 (s, 1H), 2.40 (s, 3H), 2.13 (s, 1H), 2.07(s, 1H), 2.00 (s, 1H), 1.75-1.61 (m, 8H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.20 mL) wasadded (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (43 mg, 0.07mmol), and the mixture was stirred at 55° C. The reaction was stopped,and the reaction mixture was concentrated in vacuo to remove the solventand HCl to give a light yellow solid (32 mg, 97%), which was used forthe next step without further purification.

MS (ESI, pos. ion) m/z: 507.30 [M+H]⁺.

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(20 mg, 0.04 mmol) in THF (5 mL) was added a solution of LiOH (5 mg,0.16 mmol) in water (0.5 mL). The mixture was stirred at 50° C.overnight, then acidified with hydrochloric acid (1 M) to pH about 6.The resulting mixture was extracted with 2-methyl tetrahydrofuran (15mL×3). The combined organic layers were washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1-5/1) to givethe title compound as a white solid (6 mg, 31%).

MS (ESI, pos. ion) m/z: 493.20 [M+H]⁺;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm) 12.36 (s, 1H), 8.60 (d, J=9.0 Hz, 1H),8.41 (s, 1H), 8.30 (s, 1H), 7.88 (s, 1H), 7.81 (d, J=6.5 Hz, 1H), 7.59(s, 1H), 6.86 (s, 1H), 5.33 (s, 1H), 4.64 (s, 1H), 2.03-1.96 (m, 2H),1.61 (m, 9H).

Example 24a:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 2 of example 24, using 2,4-dichloro-6-(5-nitrofuran-2-yl)pyrimidine(300 mg, 1.15 mmol), (2S,3S)-ethyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (328 mg, 1.40mmol), potassium carbonate (477 mg, 3.45 mmol) as reagents and DMF (10mL) as solvent. The title compound was a white solid (271 mg, 56%).

MS (ESI, pos. ion) m/z: 421.1 [M+H]⁺.

Step 3: (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 3 of example 24, using5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(298 mg, 0.43 mmol, 60%), K₂CO₃ (155 mg, 1.11 mmol), Pd(dppf)Cl₂ (29 mg,0.04 mmol) and (2S,3S)-ethyl3-((2-chloro-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (148 mg, 0.35 mmol) as reagents and amixture of 1,4-dioxane (8 mL) and H₂O (1 mL) as mixed solvent. The titlecompound was a white solid (125 mg, 53%).

Step 4: (2S,3S)-ethyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

The title compound can be prepared by the synthetic method described instep 4 of example 24, using (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(125 mg, 0.19 mmol) and a solution of HCl in 1,4-dioxane (4 mol/L, 0.50mL). The title compound was a light yellow solid (95 mg, 99%), which wasused in the next step without further purification.

MS (ESI, pos. ion) m/z: 521.1 [M+H]⁺.

Step 5:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

The title compound can be prepared by the synthetic method described instep 5 of example 24, using (2S,3S)-ethyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(5-nitrofuran-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(95 mg, 0.18 mmol), a solution of LiOH (17 mg, 0.72 mmol) in water (0.5mL), and solvent THF (5 mL). The title compound was a white solid (27mg, 30%).

HRMS (ESI, pos. ion) m/z: 493.1638 [M+H]⁺, (C₂₄H₂₂FN₆O₅)[M+H]⁺theoretical value: 493.1636;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.35 (s, 1H), 8.59 (d, J=8.7 Hz,1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=3.7 Hz, 1H), 7.80 (d, J=6.7Hz, 1H), 7.57 (d, J=3.2 Hz, 1H), 6.85 (s, 1H), 4.64 (s, 1H), 2.44 (s,1H), 1.99 (s, 1H), 1.96 (s, 1H), 1.77-1.39 (m, 8H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 175.82, 162.93, 162.64, 154.77,152.13, 150.63, 146.48, 132.19, 131.96, 131.71, 118.94, 115.82, 115.10,113.30, 110.03, 98.24, 50.58, 50.03, 28.69, 28.41, 25.98, 24.15, 21.28,19.36.

Example 25:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was added NaH (130 mg, 3.19 mmol, 60%) at 0° C., andthe mixture was stirred at this temperature for 30 min. Then2-iodopropane (904 mg, 5.32 mmol) was added to the mixture, and theresulting mixture was stirred at rt overnight. The reaction was quenchedwith water (50 mL), and the resulting mixture was partitioned. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The combinedorganic layers were washed with saturated brine (80 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=10/1) to give the title compound as a yellow solid (356mg, 58%).

MS (ESI, pos. ion) m/z: 231.05 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (390 mg,1.96 mmol) and 2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (410mg, 1.78 mmol) were dissolved in tetrahydrofuran (5 mL), then potassiumcarbonate (493 mg, 3.56 mmol) was added. The mixture was stirred at rtovernight. The reaction was stopped, and to the reaction mixture wasadded water (50 mL) to quench the reaction. The resulting mixture waspartitioned and the aqueous layer was extracted with ethyl acetate (50mL×2). The combined organic layers were washed with saturated brine (80mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1 to give the title compound as ayellow solid (333 mg, 50%).

MS (ESI, pos. ion) m/z: 425.15 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.39 (d, J=4.2 Hz, 1H), 7.02 (d, J=3.6Hz, 1H), 6.43 (s, 1H), 5.25 (s, 1H), 5.04 (dt, J=13.5, 6.8 Hz, 1H), 4.62(s, 1H), 3.76 (s, 3H), 2.42 (d, J=5.4 Hz, 1H), 2.02 (s, 1H), 1.95 (d,J=2.3 Hz, 1H), 1.88-1.74 (m, 2H), 1.69-1.62 (m, 5H), 1.45-1.49 (m, 6H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(200 mg, 0.48 mmol), K₂CO₃ (166 mg, 1.19 mmol), Pd(dppf)Cl₂ (32 mg, 0.04mmol) and (+/−)-trans-methyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(150 mg, 0.40 mmol) in 1,4-dioxane (8.0 mL) was added H₂O (1 mL). Theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture in a tube was sealed and stirred at 110° C. for 1.5 h. After thereaction was completed, the mixture was filtered to remove solidimpurities. Then the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatograph (PE/EtOAc (v/v)=10/1−5/1) to give awhite solid (124 mg, 49%).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of sodium hydroxide (78 mg, 1.97 mmol) in water (1 mL) wasadded to a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(124 mg, 0.20 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixturewas stirred at r.t overnight. Water (10 mL) was added. The reactionmixture was adjusted to pH about 6 with hydrochloric acid (1 M). Theresulting mixture was extracted with EtOAc (15 mL×3). The combinedorganic layers were washed with saturated brine, dried over anhydrousNa₂SO₄ and filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatograph (DCM/MeOH(v/v)=10/1-5/1) to give the title compound as a white solid (38 mg,42%).

MS (ESI, pos. ion) m/z: 463.55 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 463.2262[M+H]⁺, (C₂₅H₂₈FN₇O₂)[M+H]⁺theoretical value: 463.2258;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.08 (s, 1H), 8.68 (d, J=8.8 Hz,1H), 8.31-8.18 (m, 2H), 7.21 (d, J=2.5 Hz, 2H), 6.64 (s, 1H), 5.08-4.96(m, 1H), 4.79 (s, 1H), 2.72 (d, J=6.3 Hz, 1H), 2.03 (d, J=12.3 Hz, 2H),1.88-1.69 (m, 3H), 1.68-1.53 (m, 3H), 1.49 (dd, J=6.3, 3.3 Hz, 6H), 1.38(d, J=10.9 Hz, 2H), 1.19 (m, 1H).

Example 26:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 2.66mmol) in DMF (8 mL) was added NaH (127 mg, 3.19 mmol, 60%) at 0° C. Thereaction mixture was stirred for 30 min at 0° C., then iodomethane (3.78g, 26.60 mmol) was added. The reaction mixture was stirred at rtovernight. Water (50 mL) was added to quench the reaction, and themixture was partitioned. The aqueous layer was extracted with EtOAc (50mL×2). The combined organic layers were washed with saturated brine (80mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gelchromatograph (PE/EtOAc (v/v)=10/1) to give the title compound as ayellow solid (275 mg, 51%).

MS (ESI, pos. ion) m/z: 202.00 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.47 (d, J=3.1 Hz, 1H), 6.64 (d, J=3.0Hz, 1H), 4.16 (s, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (236 mg, 1.17 mmol) and2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (301 mg, 2.13 mmol) inTHF (5 mL) was added K₂CO₃ (301 mg, 2.16 mmol). Then the mixture wasstirred at room temperature overnight. After the reaction was completed,the reaction mixture was quenched with water (50 mL) and the resultingmixture was partitioned. The aqueous layer was extracted with ethylacetate (50 mL×2), and the combined organic layers were washed withsaturated brine (80 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo. The residue obtained was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the titlecompound as a yellow solid (122 mg, 33%).

MS (ESI, pos. ion) m/z: 350.15 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(153 mg, 0.43 mmol), K₂CO₃ (156 mg, 1.13 mmol), Pd(dppf)Cl₂ (28 mg, 0.04mmol) and (+/−)-trans-methyl3-((2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(136 mg, 0.39 mmol) in 1,4-dioxane (8.0 mL) was added H₂O (1 mL). Theair in the mixture was removed by bubbling with nitrogen for 10 min, andthen the mixture was stirred at 110° C. for 1.5 h with microwaveheating. The reaction mixture filtered through a celite pad to removesolid impurities, and the filtrate was concentrated in vacuo to removethe solvent. The residue was purified by silica gel chromatograph(PE/EtOAc (v/v)=10/1−5/1) to give the title compound as a white solid(75 mg, 32%).

MS (ESI, pos. ion) m/z: 604.40 [M+H]⁺.

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of sodium hydroxide (51 mg, 1.24 mmol) in water (1 mL) wasadded to a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(75 mg, 0.12 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixture wasstirred at rt overnight. Water (10 mL) was added. The mixture wasadjusted to pH about 6 with aqueous hydrochloric acid (1 M) solution.The resulting mixture was extracted with EtOAc (15 mL×3). The combineorganic layers were washed with saturated brine (40 mL), dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel chromatograph (DCM/MeOH(v/v)=10/1-5/1) to give the title compound as a white solid (21 mg,39%).

MS (ESI, pos. ion) m/z: 435.20 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 435.1944[M+H]⁺, (C₂₃H₂₄FN₆O₂)[M+H]⁺theoretical value: 435.1945;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.72 (s, 1H), 8.65-8.56 (m, 2H),8.38 (s, 1H), 7.64 (s, 1H), 7.11 (s, 1H), 6.47 (d, J=2.6 Hz, 1H), 5.14(s, 1H), 4.15 (s, 3H), 2.08 (s, 1H), 2.03 (s, 1H), 1.83 (d, J=8.2 Hz,3H), 1.58-1.48 (m, 5H).

Example 27:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.60mmol) in DCM (5 mL) was added phenylboronic acid (215 mg, 1.76 mmol),Cu(OAc)₂ (580 mg, 3.19 mmol) and Et₃N (1.61 g, 15.95 mmol). The mixturewas stirred at rt in oxygen atmosphere overnight. Water (50 mL) wasadded to quench the reaction, and the mixture was partitioned. Theaqueous layer was extracted with EtOAc (50 mL×2). The combined organiclayers were washed with saturated brine (80 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel chromatograph (PE/EtOAc (v/v)=10/1)to give the title compound as a yellow solid (296 mg, 70%).

MS (ESI, pos. ion) m/z: 265.35 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (245 mg,1.23 mmol) and 2,4-dichloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (296mg, 1.12 mmol) were dissolved in DMF (10 mL), then potassium carbonate(310 mg, 2.24 mmol) was added. The mixture was stirred at rt overnight.To the reaction mixture was added water (50 mL) to quench the reaction,and the resulting mixture was partitioned. The aqueous layer wasextracted with ethyl acetate (50 mL×2). The combined organic layers werewashed with saturated brine (80 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound as a yellow solid (156 mg, 34%).

MS (ESI, pos. ion) m/z: 412.15 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(185 mg, 0.42 mmol), K₂CO₃ (160 mg, 1.14 mmol), PdCl₂(dppf) (30 mg, 0.04mmol) and (+/−)-trans-methyl3-((2-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate(156 mg, 0.38 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was sealed in a tube, and stirred for 1.5 h at 110° C. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1-5/1) to give the title compound as awhite solid (135 mg, 53%).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(120 mg, 0.18 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofsodium hydroxide (78 mg, 1.81 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 6. The mixture was extracted with ethyl acetate (15mL×3), and the combined organic layers were washed with saturated brine(40 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1-5/1) to give thetitle compound as a white solid (61 mg, 68%).

MS (ESI, pos. ion) m/z: 497.15 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 497.2106[M+H]⁺, (C₂₈H₂₆FN₆O₂)[M+H]⁺theoretical value: 497.2101;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.12 (s, 1H), 8.62 (d, J=8.1 Hz,1H), 8.26 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.95 (d, J=7.8 Hz, 2H), 7.60(t, J=7.8 Hz, 2H), 7.52 (d, J=3.4 Hz, 1H), 7.45-7.38 (m, 2H), 6.90 (s,1H), 4.81 (s, 1H), 2.74 (d, J=6.3 Hz, 1H), 2.04 (d, J=15.2 Hz, 2H),1.87-1.73 (m, 3H), 1.67-1.55 (m, 3H), 1.49-1.39 (m, 3H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.15, 156.76, 156.24, 155.12,150.20, 146.42, 138.64, 131.65, 131.44, 130.44, 129.64, 126.48, 123.68,123.25, 118.99, 118.86, 115.71, 101.44, 50.64, 49.04, 28.93, 28.81,26.05, 24.25, 21.55, 19.53.

Example 28:(+/−)-trans-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was added NaH (130 mg, 3.25 mmol, 60%) at 0° C., andthe mixture was stirred at this temperature for 30 min. Then cyclopropylbromide (643 mg, 5.32 mmol) and cuprous iodide (3.19 g, 16.7 mmol) wasadded to the mixture, and the resulting mixture was stirred at 120° C.overnight. To the reaction mixture was added water (50 mL), and theresulting mixture was extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as ayellow solid (453 mg, 75%).

MS (ESI, pos. ion) m/z: 229.10 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.25 (d, J=3.6 Hz, 1H), 6.64 (d, J=3.6Hz, 1H), 6.00 (ddd, J=16.2, 10.9, 5.8 Hz, 1H), 5.31 (d, J=10.2 Hz, 1H),5.19 (d, J=17.1 Hz, 1H), 4.87 (d, J=5.7 Hz, 2H).

Step 2: (+/−)-trans-methyl3-((2-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (360 mg,1.80 mmol) and 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine(374 mg, 1.64 mmol) were dissolved in DMF (5 mL), then potassiumcarbonate (453 mg, 3.28 mmol) was added. The mixture was stirred at rtovernight. To the reaction mixture was added water (50 mL) to quench thereaction, and the resulting mixture was partitioned. The aqueous layerwas extracted with ethyl acetate (50 mL×2). The combined organic layerswere washed with saturated brine (80 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (370 mg, 60%).

MS (ESI, pos. ion) m/z: 376.15 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((7-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(172 mg, 0.41 mmol), K₂CO₃ (156 mg, 1.39 mmol), Pd(dppf)Cl₂ (28 mg, 0.05mmol) and (+/−)-trans-methyl3-((2-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate(174 mg, 0.46 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 1.5 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo to remove the solvent, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1−5/1) to give the title compound as a white solid (120 mg,41%).

Step 4:(+/−)-trans-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((7-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(120 mg, 0.19 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofNaOH (78 mg, 1.91 mmol) in water (1 mL). The mixture was stirred at rtovernight, then acidified with diluted hydrochloric acid (1 M) to pHabout 6. The resulting mixture was extracted with ethyl acetate (15mL×3). The combined organic layers were washed with saturated brine (40mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1-5/1) to givethe title compound as a white solid (43 mg, 49%).

MS (ESI, pos. ion) m/z: 461.15 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 461.2113[M+H]⁺, (C₂₅H₂₆FN₆O₂)[M+H]⁺theoretical value: 461.2101;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.17 (s, 1H), 8.65 (d, J=7.6 Hz,1H), 8.28 (s, 2H), 7.45 (s, 1H), 7.09 (s, 1H), 6.71 (s, 1H), 6.07 (s,1H), 5.19 (d, J=9.3 Hz, 1H), 5.08 (d, J=16.9 Hz, 1H), 4.87 (s, 2H), 2.72(s, 2H), 2.02 (s, 2H), 1.87-1.73 (m, 3H), 1.48-1.40 (m, 5H).

Example 29:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-5-phenyl-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (1.00 g, 5.26mmol) in DCM (5 mL) was added phenylboronic acid (710 mg, 5.79 mmol),cupric acetate (1.82 g, 10.52 mmol), Et₃N (5.32 g, 53.62 mmol). Then thereaction mixture was stirred in oxygen atmosphere at rt overnight. Water(50 mL) was added to quench the reaction, and the mixture waspartitioned. The aqueous layer was extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel chromatograph (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (1.03 g, 74%).

MS (ESI, pos. ion) m/z: 265.20 [M]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (267 mg, 1.3 mmol),2,4-dichloro-5-phenyl-5H-pyrrolo[3,2-d]pyrimidine (322 mg, 1.22 mmol) inTHF (5 mL) was added K₂CO₃ (337 mg, 2.44 mmol). Then the mixture wasstirred at room temperature overnight. The reaction mixture quenchedwith water (50 mL), and the resulting mixture was partitioned. Theaqueous layer was extracted with EtOAc (50 mL×2), and the combinedorganic layers were washed with saturated brine (80 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (150 mg, 30%).

MS (ESI, pos. ion) m/z: 411.10 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(150 mg, 0.36 mmol), K₂CO₃ (140 mg, 0.99 mmol), Pd(dppf)Cl₂ (25 mg, 0.02mmol) and (+/−)-trans-methyl3-((2-chloro-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(136 mg, 0.33 mmol) in 1,4-dioxane (8.0 mL) was added water (1 mL). Theair in the mixture was removed by bubbling with nitrogen for 10 min andthen the mixture was stirred at 110° C. for 1.5 h with microwaveheating. The reaction mixture was filtered through a celite pad toremove solid impurities, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatograph (PE/EtOAc(v/v)=10/1−5/1) to give the title compound as a white solid (185 mg,84%).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of NaOH (123 mg, 2.78 mmol) in water (1 mL) was added to asolution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-phenyl-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(185 mg, 0.28 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixturewas stirred at rt overnight. Water (10 mL) was added, and the resultingmixture was adjusted to pH about 6 with aqueous hydrochloric acidsolution (1 M). The mixture was extracted with EtOAc (15 mL×3). Thecombined organic layers were washed with saturated brine, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1-5/1) to give the title compound as a white solid(63 mg, 46%).

MS (ESI, pos. ion) m/z: 497.10 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 497.2094[M+H], (C₂₈H₂₆FN₇O₂)[M+H]⁺ theoreticalvalue: 497.2101;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 8.69 (dd, J=9.8, 2.7Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.68 (d, J=3.0Hz, 1H), 7.66-7.61 (m, 3H), 7.59 (d, J=7.6 Hz, 3H), 6.66 (d, J=3.1 Hz,1H), 4.74 (s, 1H), 2.03 (s, 1H), 1.88 (d, J=2.4 Hz, 1H), 1.83 (s, 1H),1.68 (d, J=9.2 Hz, 1H), 1.53 (m, 4H), 1.34 (m, 4H).

Example 30:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1) 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was added NaH (120 mg, 2.93 mmol, 60%) at 0° C., andthe mixture was stirred at this temperature for 30 min. Thenparatoluensulfonyl chloride (608 mg, 3.19 mmol) was added to themixture, and the resulting mixture was stirred at rt overnight. To thereaction mixture was added water (50 mL) to quench the reaction, and theresulting mixture was partitioned. The aqueous layer was extracted withethyl acetate (50 mL×2). The combined organic layers were washed withsaturated brine (80 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound as a yellow solid (780 mg, 86%).

MS (ESI, pos. ion) m/z: 343.90 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13 (d, J=8.3 Hz, 2H), 7.77 (d, J=4.0Hz, 1H), 7.38 (d, J=8.2 Hz, 2H), 6.70 (d, J=4.0 Hz, 1H), 2.45 (s, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (500 mg,2.51 mmol) and 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (780 mg,2.28 mmol) were dissolved in DMF (10 mL), then potassium carbonate (630mg, 4.56 mmol) was added. The mixture was stirred at rt overnight. Tothe reaction mixture was added water (50 mL) to quench the reaction, andthe resulting mixture was extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as ayellow solid (803 mg, 72%).

MS (ESI, pos. ion) m/z: 490.50 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.09 (d, J=8.2 Hz, 2H), 7.44 (d, J=3.9Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.48 (s, 1H), 4.52 (t, J=5.8 Hz, 1H),3.73 (s, 3H), 2.42 (s, 3H), 1.99 (s, 1H), 1.86 (s, 1H), 1.73 (s, 2H),1.70-1.37 (m, 9H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(187 mg, 0.45 mmol), K₂CO₃ (170 mg, 1.23 mmol), Pd(dppf)Cl₂ (30 mg, 0.04mmol) and (+/−)-trans-methyl3-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.41 mmol) in1,4-dioxane (8.0 mL) was added water (1 mL). The air in the mixture wasremoved by bubbling with nitrogen for 10 min, and the mixture wasstirred at 110° C. for 1.5 h. The reaction mixture was filtered througha celite pad to remove the solid impurity, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatograph (PE/EtOAc (v/v)=10/1−5/1) to give the title compound as awhite solid (292 mg, 96%).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of NaOH (120 mg, 2.84 mmol) in water (1 mL) was added to asolution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(212 mg, 0.28 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixturewas stirred at rt overnight. Water (10 mL) was added, and the reactionmixture was adjusted to pH about 6 with aqueous hydrochloric acid (1 M)solution. The mixture was extracted with EtOAc (15 mL×3). The combinedorganic layers were washed with saturated brine (40 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatograph(DCM/MeOH (v/v)=10/1-5/1) to give the title compound as a white solid(51 mg, 43%).

MS (ESI, pos. ion) m/z: 421.10 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 421.1800[M+H]⁺, (C₂₂H₂₃FN₆O₂)[M+H]⁺theoretical value: 421.1788;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.04 (s, 1H), 11.32 (s, 1H), 8.73(d, J=10.2 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.19 (d, J=6.5 Hz, 1H),7.03 (s, 1H), 6.61 (s, 1H), 4.80 (s, 1H), 2.73 (d, J=6.1 Hz, 1H), 2.02(s, 1H), 1.93-1.33 (m, 7H), 1.23 (s, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.16, 156.73, 155.99, 155.07,146.29, 131.48, 131.23, 130.08, 129.91, 129.48, 120.66, 119.06, 115.95,100.99, 99.44, 50.45, 48.94, 29.01, 28.87, 26.00, 24.14, 21.53, 19.43.

Example 31:(+/−)-trans-3-((6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (110 mg, 0.58mmol) in DMF (8 mL) was added K₂CO₃ (160 mg 1.16 mmol). The reactionmixture was stirred for 30 min at rt, and iodomethane (3.78 g, 26.60mmol) was added. The reaction mixture was stirred at rt overnight. Water(50 mL) was added to quench the reaction, and the mixture waspartitioned. The aqueous layer was extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel chromatograph (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (48 mg, 41%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.16 (s, 1H), 4.13 (s, 3H).

Step 2: (+/−)-trans-methyl3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (132 mg, 0.67 mmol) and4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (123 mg, 0.61 mmol)in THF (5 mL) was added K₂CO₃ (167 mg, 1.21 mmol). Then the mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water (50 mL), and the resulting mixture was partitioned. Theaqueous layer was extracted with EtOAc (50 mL×2). The combined organiclayers were washed with saturated brine (80 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (201 mg, 95%).

MS (ESI, pos. ion) m/z: 351.10 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.00 (s, 1H), 4.62 (t, J=6.3 Hz, 1H),3.99 (s, 3H), 3.74 (s, 3H), 2.44 (s, 1H), 1.94 (s, 1H), 1.88-1.37 (m,10H).

Step 3: (+/−)-trans-methyl3-((6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(86 mg, 0.21 mmol), K₂CO₃ (78 mg, 0.57 mmol), Pd(dppf)Cl₂ (15 mg, 0.02mmol) and (+/−)-trans-methyl3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(66 mg, 0.19 mmol) in 1,4-dioxane (8.0 mL) was added water (1 mL). Theair in the mixture was removed by bubbling with nitrogen for 10 min andthen the mixture was stirred at 110° C. for 1.5 h. The reaction mixturewas filtered through a celite pad to remove the solid impurity. Then thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatograph (PE/EtOAc (v/v)=10/1−5/1) to give the title compoundas a white solid (53 mg, 47%).

MS (ESI, pos. ion) m/z: 605.10 [M+H]⁺.

Step 4:(+/−)-trans-3-((6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of NaOH (41 mg, 0.94 mmol) in water (1 mL) was added to asolution of (+/−)-trans-methyl3-((6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(57 mg, 0.09 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixture wasstirred at rt overnight. Water (10 mL) was added to the reactionmixture, and the resulting mixture was adjusted pH to about 6 withaqueous hydrochloric acid solution (1 M). The mixture was extracted withEtOAc (15 mL×3). The combined organic layers were washed with saturatedbrine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatograph (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (33 mg, 80%).

MS (ESI, pos. ion) m/z: 436.10 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 436.1910[M+H]⁺, (C₂₂H₂₃FN₇O₂)[M+H]⁺theoretical value: 436.1897;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): ¹H NMR (600 MHz, DMSO-d₆) δ (ppm):12.27 (s, 1H), 8.68 (d, J=9.3 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.10(s, 1H), 7.99 (d, J=6.4 Hz, 1H), 4.83 (s, 1H), 3.96 (s, 3H), 2.67 (s,1H), 2.03 (s, 2H), 1.84-1.41 (m, 9H).

Example 32:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 2,4-dichloro-7-nonyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was added NaH (130 mg, 3.19 mmol) at 0° C., and themixture was stirred at this temperature for 30 min. Then bromononane(1.03 mg, 5.32 mmol) was added to the mixture, and the resulting mixturewas stirred at rt overnight. To the reaction mixture was added water (50mL), and the resulting mixture was partitioned. The aqueous layer wasextracted with ethyl acetate (50 mL×2). The combined organic layers werewashed with saturated brine (80 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound as a yellow solid (821 mg, 98%).

MS (ESI, pos. ion) m/z: 315.10 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.24 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.5Hz, 1H), 4.23 (t, J=7.3 Hz, 2H), 1.84 (dt, J=14.1, 7.2 Hz, 2H),1.31-1.23 (m, 12H), 0.87 (t, J=7.0 Hz, 3H).

Step 2: (+/−)-trans-methyl3-((2-chloro-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (572 mg, 2.87 mmol) and2,4-dichloro-7-nonyl-7H-pyrrolo[2,3-d]pyrimidine (821 mg, 2.61 mmol) inTHF (5 mL) was added DIPEA (4.6 mL, 26.13 mmol). Then the mixture wasstirred at room temperature overnight. The reaction was quenched withwater (50 mL), and the resulting mixture was partitioned. The aqueouslayer was extracted with ethyl acetate (50 mL×2). The combined organiclayers were washed with saturated brine (80 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (174 mg, 14%).

MS (ESI, pos. ion) m/z: 462.15 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a mixture of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(172 mg, 0.42 mmol), K₂CO₃ (156 mg, 1.13 mmol), Pd(dppf) Cl₂ (28 mg,0.04 mmol) and (+/−)-trans-methyl3-((2-chloro-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(174 mg, 0.38 mmol) in 1,4-dioxane (8.0 mL) was added H₂O (1 mL) under anitrogen atmosphere. The gas in the mixture was removed by bubbling withnitrogen for 10 min and then the mixture was stirred at 110° C. for 1.5h with microwave heating. The reaction mixture was filtered through acelite pad to remove solid impurities. Then the filtrate wasconcentrated in vacuo to remove the solvent. The residue was purified bysilica gel chromatograph (PE/EtOAc (v/v)=10/1−5/1) to give the titlecompound as a white solid (216 mg, 80%).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of NaOH (79 mg, 1.58 mmol) in water (1 mL) was added to asolution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-nonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(113 mg, 0.16 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixturewas stirred at rt overnight. Water (10 mL) was added to the reactionmixture, and the resulting mixture was adjusted pH to about 6 withaqueous hydrochloric acid solution (1 M). The mixture was extracted withEtOAc (15 mL×3). The combined organic layers were washed with saturatedbrine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtratewas concentrated in vacuo. The residue was purified by silica gelchromatograph (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (31 mg, 36%).

MS (ESI, pos. ion) m/z: 547.70 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 421.1800[M+H]⁺, (C₃₁H₄₀FN₆O₂)[M+H]⁺theoretical value: 421.1788;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.06 (s, 1H), 8.70 (dd, J=9.8, 2.3Hz, 1H), 8.25 (s, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.21(d, J=6.4 Hz, 1H), 7.06 (d, J=3.2 Hz, 1H), 6.62 (s, 1H), 4.78 (s, 1H),4.16 (t, J=6.6 Hz, 2H), 4.13-4.09 (m, 1H), 2.71 (d, J=6.7 Hz, 1H), 2.02(d, J=11.4 Hz, 2H), 1.89-1.71 (m, 5H), 1.58 (m, 4H), 1.37-1.17 (m, 12H),0.74 (t, J=6.6 Hz, 3H).

Example 33:(+/−)-trans-3-((7-benzyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 7-benzyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was added NaH (130 mg, 3.19 mmol, 60%) at 0° C., andthe mixture was stirred at this temperature for 30 min. Then benzylbromide (904 mg, 5.32 mmol) was added to the mixture, and the resultingmixture was stirred at rt overnight. To the reaction mixture was addedwater (50 mL), and the resulting mixture was extracted with ethylacetate (50 mL×2). The combined organic layers were washed withsaturated brine (80 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to remove the solventand the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=10/1) to give the title compound as a yellow solid (683mg, 92%).

MS (ESI, pos. ion) m/z: 279.30 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.39-7.32 (m, 3H), 7.24 (d, J=7.6 Hz,2H), 7.19 (d, J=3.6 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H), 5.43 (s, 2H).

Step 2: (+/−)-trans-methyl3-((7-benzyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (236 mg, 1.19 mmol) and2,4-dichloro-7-nonyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.08 mmol) inTHF (5 mL) was added K₂CO₃ (301 mg, 2.16 mmol). Then the mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water (50 mL), and the resulting mixture was partitioned. Theaqueous layer was extracted with EtOAc (50 mL×2). The combined organiclayers were washed with saturated brine (80 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a white solid (250 mg, 55%).

MS (ESI, pos. ion) m/z: 425.15 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.39-7.36 (m, 1H), 7.31 (dd, J=11.7,4.5 Hz, 3H), 7.20 (d, J=7.3 Hz, 2H), 6.90-6.79 (m, 1H), 6.42 (s, 1H),5.33 (d, J=8.4 Hz, 2H), 4.60 (d, J=6.0 Hz, 1H), 3.76 (s, 3H), 2.43 (d,J=5.2 Hz, 1H), 2.06 (s, 1H), 2.02 (s, 1H), 1.94 (d, J=2.3 Hz, 1H), 1.71(m, 8H).

Step 3: (+/−)-trans-methyl3-((7-benzyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(172 mg, 0.41 mmol), K₂CO₃ (156 mg, 1.13 mmol), PdCl₂(dppf) (28 mg, 0.04mmol) and (+/−)-trans-methyl3-((7-benzyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(174 mg, 0.38 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 1.5 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove the solid impuritiesThe filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1-5/1) to give thetitle compound as a white solid (89 mg, 32%).

Step 4:(+/−)-trans-3-((7-benzyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

A solution of NaOH (56 mg, 1.31 mmol) in water (1 mL) was added to asolution of (+/−)-trans-methyl3-((7-benzyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(89 mg, 0.13 mmol) in THF/MeOH (v/v=5 mL/5 mL). The reaction mixture wasstirred at r.t. overnight. Water (10 mL) was added to the reactionmixture, and the resulting mixture was adjusted pH to about 6 withaqueous HCl solution (1 M). The mixture was extracted with EtOAc (15mL×3). The combined organic layers were washed with saturated brine (40mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatograph (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (20 mg, 30%).

MS (ESI, pos. ion) m/z: 511.60 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 511.2257[M+H]⁺, (C₂₉H₂₈FN₆O₂)[M+H]⁺theoretical value: 511.2258;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.09 (s, 1H), 8.65 (d, J=8.2 Hz,1H), 8.28-8.21 (m, 2H), 7.72-7.66 (m, 4H), 7.31 (s, 2H), 7.17 (d, J=3.1Hz, 1H), 6.67 (s, 1H), 5.43 (s, 2H), 4.79 (s, 1H), 2.72 (d, J=6.6 Hz,1H), 2.02 (s, 2H), 1.84-1.47 (m, 9H).

Example 34:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1:7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine

The solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66mmol) in DMF (5 mL) was stirred at 0° C. for 5 min, then to the solutionwas added sodium hydride (130 mg, 3.19 mmol, 60%). The resulting mixturewas stirred for 15 min at 0° C., then(2-bromoethoxy)(tert-butyl)dimethylsilane (904 mg, 5.32 mmol) was added.The mixture was warmed to rt and stirred overnight. To the reactionmixture was added water (100 mL) to quench the reaction, and theresulting mixture was extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as awhite solid (516 mg, 56%).

MS (ESI, pos. ion) m/z: 346.95 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.35 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.3Hz, 1H), 4.36 (t, J=4.9 Hz, 2H), 3.92 (t, J=4.9 Hz, 2H), 0.83 (s, 9H),0.08 (s, 6H).

Step 2: (+/−)-trans-methyl3-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A suspension of7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine(516 mg, 1.49 mmol), (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (330 mg, 1.64 mmol) and K₂CO₃(411 mg, 2.98 mmol) in DMF (10 mL) was stirred at rt overnight, then thereaction was quenched with H₂O (100 mL). The mixture was extracted withethyl acetate (50 mL×3), and the combined organic layers were washedwith saturated brine (80 mL×3), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) togive the title compound as a white solid (138 mg, 19%).

MS (ESI, pos. ion) m/z: 494.10 [M+H]⁺.

Step 3: (+/−)-trans-methyl3-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(129 mg, 0.31 mmol), K₂CO₃ (120 mg, 0.84 mmol), PdCl₂(dppf) (22 mg, 0.03mmol) and (+/−)-trans-methyl 3-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(128 mg, 0.38 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 1.5 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1-5/1) to give thetitle compound as a white solid (188 mg, 90%).

MS (ESI, pos. ion) m/z: 748.15 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.75-8.69 (m, 1H), 8.67 (s, 1H), 8.32(d, J=1.7 Hz, 1H), 8.14 (d, J=8.3 Hz, 2H), 7.30 (s, 2H), 7.08 (d, J=3.4Hz, 1H), 6.36 (d, J=3.3 Hz, 1H), 5.10 (d, J=6.9 Hz, 1H), 4.90 (s, 1H),4.38 (t, J=5.4 Hz, 2H), 3.99 (t, J=5.4 Hz, 2H), 3.73 (s, 3H), 2.48 (d,J=5.5 Hz, 1H), 2.39 (s, 3H), 2.08 (s, 2H), 1.98-1.70 (m, 6H), 1.64 (s,6H), 1.53 (d, J=14.8 Hz, 2H), 0.88 (s, 9H).

Step 4: (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of hydrochloric acid in 1,4-dioxane (0.26 mL, 5 mol/L) wasadded (+/−)-trans-methyl3-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(188 mg, 0.25 mmol), and the mixture was stirred at rt overnight. Thereaction mixture was concentrated in vacuo and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1-5/1) to givethe title compound as a light yellow solid (142 mg, 89%).

MS (ESI, pos. ion) m/z: 633.20 [M+H]⁺.

Step 5:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(188 mg, 0.25 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofsodium hydroxide (93 mg, 2.24 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 6. The mixture was extracted with ethyl acetate (15mL×3), and the combined organic layers were washed with saturated brine(40 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1-5/1) to give the title compound as a white solid (66 mg,63%).

MS (ESI, pos. ion) m/z: 465.10 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 465.2042[M+H]⁺, (C₂₄H₂₆FN₆O₃)[M+H]⁺theoretical value: 465.2050;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.08 (s, 1H), 8.69 (dd, J=9.7, 2.3Hz, 1H), 8.26 (d, J=1.0 Hz, 1H), 8.21 (d, J=2.6 Hz, 1H), 7.23 (d, J=6.7Hz, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 5.00 (s, 1H),4.79 (s, 1H), 4.26 (dd, J=10.3, 5.6 Hz, 2H), 3.79 (t, J=5.7 Hz, 2H),2.72 (d, J=6.7 Hz, 1H), 2.02 (s, 2H), 1.87-1.71 (m, 3H), 1.51 (m, 5H),1.25-1.17 (m, 1H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.11, 157.13, 156.02, 155.79,154.76, 150.37, 146.42, 131.53, 131.25, 130.00, 124.59, 119.03, 118.96,116.00, 115.79, 98.73, 60.74, 50.60, 49.08, 47.01, 28.95, 26.07, 24.24,21.57, 19.51.

Example 35:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: (+/−)-cis-tert-butyl(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate

To a solution of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (362mg, 1.80 mmol) and(+/−)-cis-N-tert-butoxycarbonyl-1,3-cyclohexanediamine (350 mg, 1.63mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (677mg, 4.90 mmol). The mixture was stirred at rt overnight. The reactionmixture was diluted with H₂O (50 mL) and the resulting mixture wasextracted with EtOAc (40 mL×3). The combined organic layers were washedwith saturated brine (100 mL), dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a white solid (436 mg, 70%).

MS (ESI, pos. ion) m/z: 378.1 [M+H].

Step 2:(+/−)-cis-N-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,3-diamine

To a solution of hydrochloric acid in 1,4-dioxane (0.78 mL, 3.9 mmol, 5mol/L) was added (+/−)-cis-tert-butyl(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate (150 mg, 0.39 mmol), and the mixture was stirred atrt overnight. The reaction mixture was concentrated in vacuo to removethe solvent and to the residue was added an appropriate amount of water.The resulting mixture was adjusted with saturated aqueous sodiumcarbonate to pH 9. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate and concentrated in vacuoto dry and give the title compound as a colorless solid (110 mg, 100%).

MS (ESI, pos. ion) m/z: 280.1 [M+H]⁺.

Step 3:(+/−)-cis-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of(+/−)-cis-N¹-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,3-diamine (60 mg, 0.21 mmol) in a mixed solvent oftetrahydrofuran (4 mL) and dimethyl sulfoxide (1 mL) was addedN,N-diisopropylethylamine (0.11 mL, 0.64 mmol) and1H-1,2,3-triazole-4-carboxylic acid (48 mg, 0.43 mmol). The mixture wasstirred at rt for 10 minutes, and then HATU (163 mg, 0.43 mmol) wasadded. The resulting mixture was stirred at rt for 3 h. To the reactionmixture was added water (10 mL), and the resulting mixture was extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith saturated brine (30 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dry and give thetitle compound as a colorless solid (83 mg, 100%).

MS (ESI, pos. ion) m/z: 375.2 [M+H]⁺.

Step 4:(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(213 mg, 0.26 mmol, 50%),(+/−)-cis-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide(80 mg, 0.21 mmol), potassium carbonate (88 mg, 0.64 mmol), Pd(dppf)Cl₂(34 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) togive the title compound as a brown solid (37 mg, 28%).

MS (ESI, pos. ion) m/z: 629.2[M+H]⁺.

Step 5:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide(37 mg, 0.06 mmol) in methanol (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.12 mL, 0.6 mmol). The mixture was stirredat 30° C. overnight. To the reaction mixture was added water (10 mL),and the resulting mixture was extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as awhite solid (9 mg, 32%).

MS (ESI, pos. ion) m/z: 475.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 475.2100[M+H]⁺, (C₂₃H₂₄FN₁₀O)[M+H]⁺theoretical value: 475.2119;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 8.66 (d, J=8.5 Hz,1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.61 (s,1H), 4.31 (s, 1H), 4.05 (s, 1H), 3.69 (s, 3H), 2.25 (s, 1H), 2.10 (s,1H), 1.87 (s, 2H), 1.61-1.33 (m, 4H).

Example 36:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

Step 1:(+/−)-cis-2-amino-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a solution of(+/−)-cis-N¹-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,3-diamine(62 mg, 0.22 mmol) in a mixed solvent of tetrahydrofuran (4 mL) anddimethyl sulfoxide (1 mL) was added N,N-diisopropylethylamine (0.11 mL,0.66 mmol) and 2-aminothiazole-4-carboxylic acid (63 mg, 0.44 mmol). Themixture was stirred at rt for 10 minutes, and then HATU (168 mg, 0.44mmol) was added. The resulting mixture was stirred at rt for 3 h. To thereaction mixture was added water (10 mL), and the resulting mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layers werewashed with saturated brine (30 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to dryness to givethe title compound as a colorless solid (89.9 mg, 100%).

MS (ESI, pos. ion) m/z: 406.5[M+H]⁺.

Step 2:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(221 mg, 0.27 mmol, 50%),(+/−)-cis-2-amino-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide(90 mg, 0.22 mmol), potassium carbonate (91 mg, 0.67 mmol), Pd(dppf)Cl₂(36 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The mixture was filtered through a celite pad, andthe filter cake was washed with ethyl acetate (50 mL). The filtrate waswashed with saturated brine (50 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo to dry and theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a brown solid (56 mg, 38%).

MS (ESI, pos. ion) m/z: 629.2[M+H]⁺;

¹H NMR (400 MHz, MeOD) δ (ppm): 8.80 (d, J=8.8 Hz, 1H), 8.58 (s, 1H),8.29 (s, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.25 (s,1H), 7.04 (d, J=3.1 Hz, 1H), 6.58 (d, J=3.4 Hz, 1H), 3.86 (s, 3H), 2.83(s, 3H), 2.39 (s, 2H), 1.31 (s, 8H).

Step 3:(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide

To a solution of(+/−)-cis-2-amino-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)thiazole-4-carboxamide(88 mg, 0.08 mmol) in MeOH (1 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.16 mL, 0.8 mmol). The mixture was stirredat rt overnight, then concentrated in vacuo, and the residue was dilutedwith water (10 mL). The resulting mixture was extracted with ethylacetate (20 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated in vacuo to remove the solvent. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a white solid (26 mg, 62%).

MS (ESI, pos. ion) m/z: 506.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.1877[M+H]⁺, (C₂₄H₂₅FN₉OS)[M+H]⁺theoretical value: 506.1887;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 8.66 (d, J=8.5 Hz,1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.61 (s,1H), 4.31 (s, 1H), 4.05 (s, 1H), 3.69 (s, 3H), 2.25 (s, 1H), 2.10 (s,1H), 1.87 (s, 2H), 1.61-1.33 (m, 4H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 168.62, 160.44, 156.72, 156.03,155.54, 155.13, 146.44, 146.19, 131.47, 131.27, 130.19, 124.68, 118.97,116.03, 115.88, 111.66, 99.02, 47.64, 32.27, 32.15, 31.09, 29.44, 23.52,14.42.

Example 37:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

Step 1:(+/−)-cis-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a solution of(+/−)-cis-N¹-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,3-diamine(110.5 mg, 9 mmol) in a mixed solvent of tetrahydrofuran (4 mL) anddimethyl sulfoxide (1 mL) was added N,N-diisopropylethylamine (0.16 mL,1.19 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (99 mg, 0.78mmol). The mixture was stirred at rt for 10 minutes, and then HATU (300mg, 0.79 mmol) was added. The resulting mixture was stirred at rt for 3h. To the reaction mixture was added water (10 mL), and the resultingmixture was extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with saturated brine (30 mL), dried over anhydroussodium sulfate and concentrated in vacuo to give the title compound as acolorless solid (86 mg, 56%).

MS (ESI, pos. ion) m/z: 388.2 [M+H]⁺;

¹H NMR (400 MHz, MeOD) (ppm) δ: 7.65 (d, J=6.1 Hz, 2H), 6.99 (d, J=3.3Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.68 (s,2H), 2.34 (d, J=11.6 Hz, 1H), 2.06 (s, 2H), 1.93 (d, J=13.6 Hz, 1H),1.61 (d, J=13.5 Hz, 1H), 1.44 (d, J=11.7 Hz, 1H), 1.39 (d, J=3.6 Hz,2H).

Step 2:(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(249 mg, 0.30 mmol, 50%),(+/−)-cis-N-(3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide(97 mg, 0.25 mmol), potassium carbonate (103 mg, 0.75 mmol), Pd(dppf)Cl₂(40 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The the airin the mixture was removed by bubbling with nitrogen for 10 min, thenthe mixture in the microwave tube was stirred at 120° C. with microwaveheating for 4 hours. The reaction mixture was filtered through a celitepad and the filter cake was washed with ethyl acetate (50 mL). Thefiltrate was washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a brown solid (130 mg, 81%).

MS (ESI, pos. ion) m/z: 642.3[M+H]⁺.

Step 3:(+/−)-cis-N-(3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-meth-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide

To a solution of(+/−)-cis-N-(3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide(130 mg, 0.20 mmol) in methanol (2 mL) was added a solution of sodiummethoxide in methanol (5 M, 0.40 mL, 2.00 mmol). The mixture was stirredat 30° C. overnight, then concentrated in vacuo to dry. To the reactionmixture was added water (10 mL), and the resulting mixture was extractedwith ethyl acetate (20 mL×3), and the combined organic layers werewashed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, then filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a yellow solid (70 mg, 71%).

MS (ESI, pos. ion) m/z: 488.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 488.2345[M+H]⁺, (C₂₅H₂₇FN₉O)[M+H]⁺ theoreticalvalue: 488.2323;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.10 (s, 1H), 8.68 (d, J=7.9 Hz,1H), 8.34-8.20 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.63 (d, J=11.7 Hz, 2H),7.28 (d, J=7.4 Hz, 1H), 7.05 (d, J=3.1 Hz, 1H), 6.59 (d, J=3.2 Hz, 1H),4.31 (s, 1H), 3.98 (d, J=8.3 Hz, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 2.26(d, J=10.6 Hz, 1H), 2.12 (d, J=10.7 Hz, 1H), 1.87 (d, J=10.3 Hz, 2H),1.54-1.21 (m, 4H).

Example 38:(+/−)-trans-3-((5-fluoro-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 2-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.78 mmol)in DMF (8 mL) was added bromine (0.22 mL, 4.16 mmol). The reactionmixture was stirred at r.t. for 4 h. A saturated aqueous Na₂S₂O₃solution (100 mL) was added, and the resulting mixture was extractedwith EtOAc (100 mL×2). The combined organic phases were washed withsaturated brine (100 mL×3), dried over Na₂SO₄, filtered, and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatograph (PE/EtOAc (v/v)=4/1) to give the title compound as ayellow solid (679 mg, 85%).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.19 (s, 1H), 8.27 (d, J=4.8 Hz,1H), 7.82 (d, J=7.8 Hz, 1H), 7.15 (dd, J=7.8, 4.9 Hz, 1H), 2.56 (s, 3H).

Step 2: 3-bromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg,0.47 mmol) in THF (5 mL) was added NaH (22 mg, 0.57 mmol, 60%) at 0° C.Then the reaction mixture was stirred for 30 min at 0° C. TsCl (100 mg,0.52 mmol) was added and the reaction mixture was stirred at rtovernight. Water (50 mL) was added to quench the reaction, and theresulting mixture was partitioned. The aqueous layer was extracted withEtOAc (50 mL×2). The combined organic phases were washed with saturatedbrine (80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtratewas concentrated in vacuo. The residue was purified by silica gelchromatograph (PE/EtOAc (v/v)=4/1) to give the title compound as ayellow solid (100 mg, 58%).

MS (ESI, pos. ion) m/z: 365.95 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44 (d, J=4.7 Hz, 1H), 8.04 (d, J=8.3Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.24 (dd,J=7.8, 4.9 Hz, 1H), 2.79 (s, 3H), 2.39 (s, 3H).

Step 3:2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

The air in the suspension of3-bromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.27 mmol),Pd(dppf)Cl₂ (20 mg, 0.03 mmol) and KOAc (80 mg, 0.82 mmol) in DME (5 mL)was exchanged with nitrogen and then to the mixture was addedbis(pinacolato)diboron (104 mg, 0.41 mmol). The the mixture was purgedwith nitrogen by bubbling for 10 min to remove the air, then the mixturewas stirred at 105° C. for 2 h with microwave heating. To the reactionmixture was added ethyl acetate (20 mL), and the mixture was filteredthrough a celite pad. The filter cake was washed with ethyl acetate (20mL×2). The combined filtrates was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) togive the title compound as a yellow solid (60 mg, 53%).

MS (ESI, pos. ion) m/z: 413.45 [M+H]⁺.

Step 4: (+/−)-trans-methyl3-((5-fluoro-2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (10 mL) were added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(50 mg, 0.12 mmol), K₂CO₃ (50 mg, 0.36 mmol), PdCl₂(dppf) (10 mg, 0.01mmol) and methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (41 mg, 0.13 mmol). Then H₂O (1 mL)was added to the mixture, and the air in the mixture was removed bybubbling with nitrogen for 10 min. The mixture was stirred for 1.5 h at110° C. with microwave heating for 10 min. The mixture was filteredthrough a celite pad to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1−5/1) to give the title compound as awhite solid (18 mg, 26%).

Step 5:(+/−)-trans-3-((5-fluoro-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(130 mg, 0.23 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofNaOH (95 mg, 2.31 mmol) in water (1 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 6. The resultingmixture was extracted with ethyl acetate (15 mL×3). The combined organiclayers were washed with saturated brine (40 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (32 mg, 35%).

MS (ESI, pos. ion) m/z: 396.15 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 396.1836[M+H]⁺, (C₂₁H₂₃FN₅O₂)[M+H]⁺theoretical value: 396.1836;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 8.61 (d, J=7.7 Hz,1H), 8.43 (d, J=4.9 Hz, 1H), 8.34 (d, J=4.5 Hz, 1H), 8.28 (s, 1H), 7.24(dd, J=7.5, 4.8 Hz, 1H), 4.76 (t, J=6.6 Hz, 1H), 2.90 (d, J=6.8 Hz, 1H),2.81 (s, 3H), 2.02 (s, 1H), 1.89 (s, 1H), 1.76 (d, J=8.2 Hz, 2H), 1.66(d, J=10.6 Hz, 1H), 1.59 (d, J=6.2 Hz, 1H), 1.54-1.31 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 175.75, 156.88, 152.63, 146.57,143.67, 142.67, 142.10, 141.59, 130.17, 120.33, 117.15, 107.09, 51.22,47.55, 29.18, 28.65, 25.58, 24.18, 21.48, 19.49, 14.49.

Example 39:(+/−)-trans-3-((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (10 mL) were added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(100 mg, 0.24 mmol), K₂CO₃ (100 mg, 0.73 mmol), Pd(dppf)Cl₂ (18 mg, 0.03mmol) and (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(99 mg, 0.27 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 3 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1−5/1) to give thetitle compound as a white solid (130 mg, 86%).

MS (ESI, pos. ion) m/z: 623.15 [M+H]⁺.

Step 2:(+/−)-trans-3-((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(130 mg, 0.21 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofsodium hydroxide (85 mg, 2.09 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 6. The mixture was extracted with ethyl acetate (15mL×3), and the combined organic layers were washed with saturated brine(40 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1-5/1) to give the title compound as a white solid (38 mg,40%).

MS (ESI, pos. ion) m/z: 454.20 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 454.2261 [M+H]⁺, (C₂₇H₂₈N₅O₂)[M+H]⁺theoretical value: 454.2243;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 11.91 (s, 1H), 8.90 (d, J=7.1 Hz,1H), 8.21-8.15 (m, 1H), 8.09 (d, J=6.6 Hz, 2H), 7.58-7.48 (m, 3H), 7.40(d, J=5.5 Hz, 1H), 7.14 (dd, J=7.8, 4.7 Hz, 1H), 6.71 (s, 1H), 3.94 (s,1H), 2.96 (s, 3H), 1.85-1.51 (m, 8H), 1.23 (d, J=3.1 Hz, 4H).

Example 40:(+/−)-trans-3-((7-methyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((7-methyl-2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-b]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(100 mg, 0.24 mmol), K₂CO₃ (100 mg, 0.73 mmol), Pd(dppf)Cl₂ (24 mg, 0.02mmol) and (+/−)-trans-methyl3-((2-chloro-7-methyl-7H-pyrrolo[2,3-b]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(99 mg, 0.27 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 1.5 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1−5/1) to give thetitle compound as a white solid (112 mg, 77%).

MS (ESI, pos. ion) m/z: 599.20 [M+H]⁺.

Step 2:(+/−)-trans-3-((7-methyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((7-methyl-2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7H-pyrrolo[2,3-b]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(113 mg, 0.19 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofsodium hydroxide (79 mg, 1.89 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid topH about 6. The mixture was extracted with ethyl acetate (15 mL×3), andthe combined organic layers were washed with saturated brine (40 mL),dried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (31 mg, 38%).

MS (ESI, pos. ion) m/z: 431.15 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 431.2201 [M+H]⁺, (C₂₄H₂₇N₆O₂)[M+H]⁺theoretical value: 431.2195;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm) 11.73 (s, 1H), 8.95 (d, J=7.7 Hz, 1H),8.15 (d, J=4.4 Hz, 1H), 7.16 (d, J=7.1 Hz, 1H), 7.10 (dd, J=7.8, 4.7 Hz,1H), 7.06 (d, J=3.2 Hz, 1H), 6.60 (s, 1H), 4.83 (s, 1H), 3.77 (s, 3H),2.94 (s, 3H), 2.74 (d, J=6.7 Hz, 1H), 2.00 (d, J=15.2 Hz, 2H), 1.76 (d,J=10.5 Hz, 2H), 1.62-1.34 (m, 5H), 1.24 (s, 2H).

Example 41:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 3-bromo-5-fluoropyridin-2-amine

To a solution of 5-fluoropyridin-2-amine (6 g, 53.52 mmol) inacetonitrile (120 mL) was added slowly NBS (12.64 g, 69.60 mmol), andthe mixture was stirred at rt for 2 h, then concentrated in vacuo todry. The residue was purified by silica gel column chromatography (PE/EA(v/v)=20/1) to give the title compound as a yellow solid (5.4 g, 53%).

MS (ESI, pos. ion) m/z: 193.0[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.95 (d, J=2.5 Hz, 1H), 7.52 (dd,J=7.3, 2.6 Hz, 1H), 4.84 (s, 2H).

Step 2: 5-fluoro-3-((4-fluorophenyl)ethynyl)pyridin-2-amine

To a solution of 3-bromo-5-fluoropyridin-2-amine (1.33 g, 6.96 mmol) inacetonitrile (14 mL) was added triethylamine (14 mL),1-ethynyl-4-fluorobenzene (850 mg, 7.08 mmol) and Pd(PPh₃)₂Cl₂ (496 mg,0.70 mmol) in turn, and the mixture was stirred at 75° C. for 6 h undernitrogen protection, then concentrated in vacuo to dry. The residue waspurified by silica gel column chromatography (PE/EA (v/v)=10/1) to givethe title compound as a yellow solid (770 mg, 48.0%).

MS (ESI, pos. ion) m/z: 231.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.95 (d, J=2.9 Hz, 1H), 7.56-7.48 (m,2H), 7.38 (dd, J=8.3, 2.9 Hz, 1H), 7.09 (dd, J=11.0, 4.3 Hz, 2H), 4.96(s, 2H).

Step 3: 5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-fluoro-3-((4-fluorophenyl)ethynyl)pyridin-2-amine (50mg, 0.22 mmol) in DMF (1 mL) was added potassium tert-butoxide (73 mg,0.65 mmol), and the mixture was stirred at 80° C. for 3 h under nitrogenprotection, then cooled to rt. To the reaction mixture was added water(25 mL), and the resulting mixture was extracted with ethyl acetate (25mL×3). The combined organic layers were washed with saturated brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EA (v/v)=2/1) to give the title compound as a whitesolid (30 mg, 60%).

MS (ESI, pos. ion) m/z: 231.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 12.29 (s, 1H), 8.19 (s, 1H), 8.00 (dd,J=8.6, 5.4 Hz, 2H), 7.83 (dd, J=9.5, 2.6 Hz, 1H), 7.34 (t, J=8.8 Hz,2H), 6.92 (s, 1H).

Step 4: 3-bromo-5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine(30 mg, 0.13 mmol) in DMF (1 mL) was added bromine (0.02 mL, 0.26 mmol).The reaction mixture was stirred at rt for 2 h. A saturated aqueousNa₂S₂O₃ solution (20 mL) was added, and the resulting mixture wasextracted with EtOAc (20 mL×2). The combined organic phases were washedwith saturated brine (20 mL×3), dried over anhydrous Na₂SO₄, filtered,and the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatograph (n-hexane/EtOAc (v/v)=2/1) to give the titlecompound as a white solid (15 mg, 37%).

MS (ESI, pos. ion) m/z: 311.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.65 (s, 1H), 8.32 (s, 1H), 7.94(dd, J=8.6, 5.5 Hz, 2H), 7.76 (dd, J=8.8, 2.5 Hz, 1H), 7.43 (t, J=8.8Hz, 2H).

Step 5:3-bromo-5-fluoro-2-(4-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To dried tetrahydrofuran (10 mL) was added3-bromo-5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine (0.74 g,2.0 mmol). Sodium hydride (232 mg, 5.80 mmol, 60%) was added to thesolution at 0° C., and the resulting mixture was stirred at 0° C. for 30min. Then p-toluenesulfonyl chloride (667 mg, 3.50 mmol) was added tothe mixture, and the mixture was warmed to rt and stirred for 3 h. Water(100 mL) was added to quench the reaction, and the resulting mixture wasextracted with EtOAc (100 mL×2). The combined organic phases were driedover anhydrous Na₂SO₄, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatograph (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (360 mg, 27%).

MS (ESI, pos. ion) m/z: 463.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.42 (d, J=1.2 Hz, 1H), 7.76 (d, J=8.2Hz, 2H), 7.53-7.47 (m, 3H), 7.28-7.19 (m, 4H).

Step 6:5-fluoro-2-(4-fluorophenyl)-1-tosyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine

A microwave tube was charged with3-bromo-5-fluoro-2-(4-fluorophenyl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(300 mg, 0.65 mmol), bis(pinacolato)diboron (247 mg, 0.97 mmol),potassium acetate (128 mg, 1.30 mmol), Pd(dppf)Cl₂ (53 mg, 0.06 mmol)and dimethoxyethane (4 mL). The air in the mixture was removed bybubbling with nitrogen for 10 min and stirred at 130° C. for 2 h withmicrowave heating. The mixture was cooled to rt and filtered through acelite pad. The filter cake was ethyl acetate (10 mL), and the combinedfiltrates were dried in vacuo to dry. The residue was purified by silicagel chromatograph (n-hexane/EtOAc (v/v)=10/1) to give the title compoundas yellow oil (220 mg, 67%).

MS (ESI, pos. ion) m/z: 511.4 [M+H]⁺.

Step 7: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-2-(4-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tub were added5-fluoro-2-(4-fluorophenyl)-1-tosyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(200 mg, 0.38 mmol), (+/−)-trans-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol),Pd(dppf)Cl₂ (52 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The mixture was stirred at 110° C. for 3 h. The mixture was filteredthrough a celite pad, and the filter cake was washed with ethyl acetate(50 mL). The filtrate was washed with saturated brine (50 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=5/1) to give the title compound asa yellow solid (204 mg, 97%).

MS (ESI, pos. ion) m/z: 662.1[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=2.0 Hz, 1H), 8.19 (dd,J=8.8, 2.8 Hz, 1H), 7.96 (d, J=3.1 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 1H),7.43 (s, 2H), 7.13 (t, J=8.5 Hz, 2H), 3.81 (s, 1H), 3.60 (s, 3H), 2.37(s, 3H), 2.25 (d, J=7.1 Hz, 1H), 1.58 (m, 8H).

Step 8:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-2-(4-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.30 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added aqueous sodiumhydroxide solution (4 M, 0.75 mL, 3.00 mmol). The mixture was stirred at30° C. overnight, then diluted with water (10 mL). The resulting mixturewas acidified with hydrochloric acid (1 M) to pH about 5.5, thenextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the titlecompound as a yellow solid (74 mg, 50%). HRMS (ESI, pos. ion) m/z:494.1824 [M+H]⁺, (C₂₆H₂₃F3N₅O₂)[M+H]⁺ theoretical value: 494.1804;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.35 (s, 1H), 8.41 (dd, J=9.9, 2.6Hz, 1H), 8.26 (s, 1H), 8.11 (d, J=3.6 Hz, 1H), 7.95 (s, 1H), 7.67 (dd,J=8.3, 5.6 Hz, 2H), 7.48 (d, J=7.0 Hz, 1H), 7.26 (t, J=8.8 Hz, 2H), 4.24(t, J=7.1 Hz, 1H), 2.76 (d, J=7.3 Hz, 1H), 1.94 (s, 1H), 1.66 (d, J=8.5Hz, 2H), 1.50 (s, 1H), 1.37-1.20 (m, 6H).

Example 42:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 5-fluoro-3-(2-phenylethynyl)pyridin-2-amine

To a solution of 3-bromo-5-fluoropyridin-2-amine (3.8 g, 20 mmol) inacetonitrile (40 mL) was added triethylamine (40 mL), phenylacetylene(2.2 g, 22 mmol) and Pd(PPh₃)₂Cl₂ (1.5 g, 2.1 mmol) in turn, and themixture was stirred at 75° C. for 5 h under nitrogen protection, thenconcentrated in vacuo to dry. The residue was purified by silica gelcolumn chromatography (PE/EA (v/v)=10/1) to give the title compound as ayellow solid (2.9 g, 69%).

MS (ESI, pos. ion) m/z: 213.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.95 (d, J=2.9 Hz, 1H), 7.56-7.48 (m,2H), 7.38 (dd, J=8.3, 2.9 Hz, 1H), 7.09 (dd, J=11.0, 4.3 Hz, 2H), 4.96(s, 2H).

Step 2: 5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-fluoro-3-(2-phenylethynyl)pyridin-2-amine (2.8 g, 13mmol) in DMF (30 mL) was added potassium tert-butoxide (4.4 g, 39 mmol),and the mixture was stirred at 80° C. for 3 h under nitrogen protection,then cooled to rt. To the reaction mixture was added water (25 mL), andthe resulting mixture was extracted with ethyl acetate (25 mL×3). Thecombined organic layers were washed with saturated brine (50 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EA (v/v)=2/1) to give the title compound as a whitesolid (2.5 g, 89%).

MS (ESI, pos. ion) m/z: 213.1 [M+H]⁺.

Step 3: 3-bromo-5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridine (2.5 g, 30mmol) in DMF (30 mL) was added bromine (1.2 mL, 23 mmol). The reactionmixture was stirred at rt for 2 h. A saturated aqueous Na₂S₂O₃ solution(50 mL) was added to quench the reaction, and the resulting mixture wasextracted with EtOAc (50 mL×2). The combined organic phases were washedwith saturated brine (20 mL×3), dried over anhydrous Na₂SO₄, filtered,and the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatograph (n-hexane/EtOAc (v/v)=2/1) to give the titlecompound as a white solid (3.20 g, 93%).

MS (ESI, pos. ion) m/z: 291.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.92 (s, 1H), 8.14 (s, 1H), 7.94 (d,J=7.3 Hz, 2H), 7.65 (dd, J=8.4, 2.4 Hz, 1H), 7.60 (t, J=7.5 Hz, 2H),7.53 (d, J=7.4 Hz, 1H).

Step 4: 3-bromo-5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 3-bromo-5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridine(3.84 g, 13.2 mmol) in dried tetrahydrofuran (40 mL) was added sodiumhydride (1.07 g, 26.8 mmol, 60%). The reaction mixture was stirred at 0°C. for 30 min, then p-toluenesulfonyl chloride (3.03 g, 15.9 mmol) wasadded. The resulting mixture was stirred at rt for 3 h, then quenchedwith water (100 mL), and the mixture was partitioned. The aqueous layerwas extracted with EtOAc (100 mL×2). The combined organic phases weredried over anhydrous Na₂SO₄, filtered, and the filtrate was concentratedin vacuo to dry. The residue was purified by silica gel chromatograph(n-hexane/EtOAc (v/v)=10/1) to give the title compound as a yellow solid(1.42 g, 24%).

MS (ESI, pos. ion) m/z: 444.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.41 (d, J=1.3 Hz, 1H), 7.79 (s, 1H),7.77 (s, 1H), 7.56-7.49 (m, 6H), 7.23 (d, J=8.1 Hz, 2H), 2.39 (s, 3H).

Step 5:5-fluoro-2-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A microwave tube was charged with3-bromo-5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.35 g,3.03 mmol), bis(pinacolato)diboron (1.15 g, 4.53 mmol), potassiumacetate (596 mg, 6.07 mmol), Pd(dppf)Cl₂ (249 mg, 0.30 mmol) anddimethoxyethane (10 mL). The mixture was stirred at 130° C. for 2 h withmicrowave heating. The mixture was cooled to rt and filtered through acelite pad. The filter cake was washed with ethyl acetate (10 mL), andthe combined filtrates were dried in vacuo to dry. The residue waspurified by silica gel chromatograph (n-hexane/EtOAc (v/v)=10/1) to givethe title compound as a white solid (1.14 g, 76%).

MS (ESI, pos. ion) m/z: 493.1 [M+H]⁺.

Step 6: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tube were added5-fluoro-2-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(158 mg, 0.31 mmol), (+/−)-trans-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(80 mg, 0.25 mmol), potassium carbonate (106 mg, 0.77 mmol), Pd(dppf)Cl₂(42 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min and themixture was stirred at 110° C. for 2 h. The mixture was filtered througha celite pad, and the filter cake was washed with ethyl acetate (50 mL).The filtrate was washed with saturated brine (50 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(29 mg, 18%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=1.8 Hz, 1H), 8.19 (dd,J=8.7, 2.8 Hz, 1H), 7.95 (d, J=3.0 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.44(d, J=6.0 Hz, 5H), 7.21 (d, J=8.0 Hz, 2H), 4.85 (d, J=7.4 Hz, 1H), 4.08(t, J=6.8 Hz, 1H), 3.59 (s, 3H), 2.37 (s, 3H), 2.22 (d, J=6.6 Hz, 1H),2.04 (s, 2H), 1.57-1.28 (m, 8H).

Step 7:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(29 mg, 0.05 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added aqueous sodiumhydroxide solution (4 M, 0.13 mL, 0.50 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give thetitle compound as a yellow solid (19 mg, 89%).

MS (ESI, pos. ion) m/z: 476.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 476.1900 [M+H]⁺, (C₂₆H₂₄F2N₅O₂)[M+H]⁺theoretical value: 476.1898;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.31 (s, 1H), 8.38 (dd, J=9.9, 2.7Hz, 1H), 8.26 (s, 1H), 8.08 (d, J=3.7 Hz, 1H), 7.61 (d, J=6.9 Hz, 2H),7.51-7.37 (m, 4H), 4.28 (s, 1H), 2.76 (d, J=6.8 Hz, 1H), 1.93 (s, 1H),1.66 (d, J=8.5 Hz, 2H), 1.57-1.28 (m, 8H).

Example 43:(+/−)-trans-3-((2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tube were added5-fluoro-2-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(133 mg, 0.26 mmol), (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(80 mg, 0.22 mmol), potassium carbonate (90 mg, 0.65 mmol), Pd(dppf)Cl₂(36 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min, then themixture in the sealed tube was stirred at 110° C. for 3 hours. Themixture was filtered through a celite pad, and the filter cake waswashed with ethyl acetate (50 mL). The filtrate was washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (57 mg, 38%).

MS (ESI, pos. ion) m/z: 702.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.48 (d, J=9.0 Hz, 1H), 8.43 (s, 1H),7.85 (d, J=8.2 Hz, 2H), 7.55-7.47 (m, 6H), 7.39 (d, J=6.8 Hz, 1H),7.36-7.31 (m, 2H), 7.22 (d, J=8.1 Hz, 2H), 6.63 (s, 1H), 4.92 (s, 1H),4.35 (s, 1H), 3.67 (s, 3H), 2.41-2.31 (m, 4H), 1.88 (s, 1H), 1.83-1.59(m, 8H).

Step 2:(+/−)-trans-3-((2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(51 mg, 0.07 mmol) in THF/MeOH (v/v=1/1, 1.0 mL) was added aqueoussodium hydroxide solution (4 M, 0.15 mL, 0.70 mmol). The mixture wasstirred at 30° C. overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 5.5. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1)to give the title compound as a yellow solid (35 mg, 90%).

MS (ESI, pos. ion) m/z: 534.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 534.2317 [M+H]⁺, (C₃₂H₂₉FN₅O₂)[M+H]⁺theoretical value: 534.2305;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.38 (s, 1H), 8.63 (s, 1H), 8.28 (s,1H), 7.72-7.63 (m, 2H), 7.60 (d, J=7.4 Hz, 2H), 7.50-7.31 (m, 7H), 6.71(s, 1H), 4.50 (s, 1H), 2.89 (s, 1H), 2.73 (s, 1H), 1.99 (s, 1H), 1.79(s, 1H), 1.76-1.40 (m, 8H).

Example 44:(+/−)-trans-3-((2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tube were added5-fluoro-2-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(174 mg, 0.34 mmol), (+/−)-trans-methyl3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate(100 mg, 0.29 mmol), potassium carbonate (118 mg, 0.86 mmol),Pd(dppf)Cl₂ (47 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The air in the mixture was removed by bubbling with nitrogen for 10 minand the mixture was stirred at 110° C. for 3 h. The mixture was filteredthrough a celite pad, and the filter cake was washed with ethyl acetate(50 mL). The filtrate was washed with saturated brine (50 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=5/1) to give the title compound asa yellow solid (58 mg, 30%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.52 (dd, J=9.0, 2.8 Hz, 1H), 8.41 (d,J=2.0 Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.52 (d, J=6.6 Hz, 2H),7.47-7.39 (m, 3H), 7.23 (s, 1H), 7.21 (s, 1H), 6.84 (d, J=3.4 Hz, 1H),6.32 (d, J=3.2 Hz, 1H), 4.80 (d, J=7.6 Hz, 1H), 4.62 (t, J=7.1 Hz, 1H),3.59 (s, 3H), 3.41 (s, 3H), 2.38 (s, 3H), 2.33 (d, J=6.6 Hz, 1H), 1.92(s, 2H), 1.71-1.63 (m, 6H), 1.49 (d, J=10.6 Hz, 2H).

Step 2:(+/−)-trans-3-((2-(5-fluoro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(58 mg, 0.09 mmol) in THF/MeOH (v/v=1/1, 1.0 mL) was added a solution ofsodium hydroxide in water (4 M, 0.23 mL, 0.90 mmol). The mixture wasstirred at 30° C. overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 5.5. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1)to give the title compound as a yellow solid (29 mg, 66%).

MS (ESI, pos. ion) m/z: 511.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 511.2267 [M+H]⁺, (C₂₉H₂₈FN₆O₂)[M+H]⁺theoretical value: 511.2258;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.21 (s, 1H), 8.61 (d, J=8.0 Hz,1H), 8.25 (s, 1H), 7.71 (d, J=6.8 Hz, 2H), 7.48-7.37 (m, 3H), 7.18 (d,J=6.9 Hz, 1H), 7.04 (d, J=3.3 Hz, 1H), 6.58 (d, J=2.9 Hz, 1H), 4.53 (t,J=6.9 Hz, 1H), 3.49 (s, 3H), 2.66 (d, J=7.1 Hz, 1H), 1.97 (s, 1H),1.79-1.66 (m, 4H), 1.49-1.29 (m, 6H).

Example 45:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 5-fluoro-3-iodo-4-methylpyridin-2-amine

To a solution of 5-fluoro-4-methylpyridin-2-amine (2.00 g, 15.9 mmol) inglacial acetic acid (13 mL) were added trifluoroacetic acid (0.13 mL)and NIS (3.75 g, 16.2 mmol). The mixture was stirred at rt overnight,then poured into ice water (50 mL). The resulting mixture was adjustedwith concentrated ammonia to pH9, then filtered. The filter cake waswashed with water and dried in vacuo to give a yellow solid (2.87 g,72%).

MS (ESI, pos. ion) m/z: 252.9[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.83 (s, 1H), 4.89 (s, 3H), 2.37 (d,J=2.0 Hz, 2H).

Step 2: 5-fluoro-4-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a solution of 5-fluoro-3-iodo-4-methylpyridin-2-amine (2.88 g, 11.4mmol) in a mixed solvent of triethylamine (58 mL) and tetrahydrofuran(11.6 mL) were added Pd(PPh₃)₂Cl₂ (810 mg, 1.14 mmol), cuprous iodide(435 mg, 2.28 mmol) and trimethylsilylacetylene (3.23 mL, 22.9 mmol).The mixture was stirred at rt overnight under nitrogen protection anddiluted with saturated aqueous ammonium chloride solution (100 mL). Theresulting mixture was extracted with ethyl acetate (100 mL×3), and thecombined organic layers were washed with saturated brine (200 mL), driedover anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1) to givethe title compound as a dark solid (1.72 g, 68%).

MS (ESI, pos. ion) m/z: 223.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.83 (s, 1H), 2.33 (d, J=1.4 Hz, 3H),0.30 (s, 9H).

Step 3: 5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridine

To a solution of5-fluoro-4-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.72 g,7.74 mmol) in DMF (16 mL) was added potassium tert-butoxide (2.60 g,23.2 mmol), and the mixture was stirred at 80° C. for 1 h under nitrogenprotection, then cooled to rt. To the reaction mixture was added water(100 mL), and the resulting mixture was extracted with ethyl acetate(100 mL×3). The combined organic layers were washed with saturatedbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (PE/EA (v/v)=5/1) to give the title compound as awhite solid (550 mg, 47%).

MS (ESI, pos. ion) m/z: 151.1 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 9.62 (s, 1H), 8.16 (d, J=2.2 Hz, 1H),7.42-7.33 (m, 1H), 6.53 (dd, J=3.1, 2.1 Hz, 1H), 2.53 (d, J=1.0 Hz, 3H).

Step 4: 3-bromo-5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridine (540 mg,3.60 mmol) in DMF (8 mL) was added bromine (0.37 mL, 7.19 mmol). Thereaction mixture was stirred at rt for 2 h. A saturated aqueous Na₂S₂O₃solution (50 mL) was added to quench the reaction, and the resultingmixture was extracted with EtOAc (50 mL×3). The combined organic phaseswere washed with saturated brine (50 mL×3), dried over anhydrous Na₂SO₄,filtered, and the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatograph (n-hexane/EtOAc (v/v)=5/1) to givethe title compound as a white solid (760 mg, 92%).

MS (ESI, pos. ion) m/z: 231.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 8.20 (d, J=1.7 Hz,1H), 7.72 (d, J=2.6 Hz, 1H), 2.66 (s, 3H).

Step 5: 3-bromo-5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To dried tetrahydrofuran (10 mL) was added3-bromo-5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridine (760 mg, 3.32 mmol).Sodium hydride (265 mg, 6.63 mmol, 60%) was added to the solution at 0°C., and the resulting mixture was stirred at 0° C. for 30 min. Thenp-toluenesulfonyl chloride (759 mg, 3.98 mmol) was added to the mixture,and the mixture was warmed to rt and stirred overnight. Water (100 mL)was added to quench the reaction, and the resulting mixture wasextracted with EtOAc (100 mL×3). The combined organic phases were driedover anhydrous Na₂SO₄, filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatograph(n-hexane/EtOAc (v/v)=10/1) to give the title compound as a yellow solid(840 mg, 66%).

MS (ESI, pos. ion) m/z: 382.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.24 (s, 1H), 8.06 (d, J=8.3 Hz, 2H),7.81 (s, 1H), 7.31 (d, J=8.2 Hz, 2H), 2.68 (d, J=1.3 Hz, 3H), 2.40 (s,3H).

Step 6:5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

A microwave tube was charged with3-bromo-5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (400 mg,1.04 mmol), bis(pinacolato)diboron (397 mg, 1.56 mmol), potassiumacetate (204 mg, 2.08 mmol), Pd(dppf)Cl₂ (85 mg, 0.10 mmol) anddimethoxyethane (5 mL). The air in the mixture was removed by bubblingwith nitrogen for 10 min and the mixture was stirred at 130° C. for 2 hwith microwave heating. The mixture was cooled to rt and filteredthrough a celite pad. The filter cake was washed with ethyl acetate (10mL) and the combined filtrates were concentrated in vacuo to dry. Theresidue was purified by silica gel chromatograph (n-hexane/EtOAc(v/v)=10/1) to give the title compound as a white solid (352 mg, 78%).

MS (ESI, pos. ion) m/z: 431.0 [M+H]⁺.

Step 7: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tub were added5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(163 mg, 0.38 mmol), (+/−)-trans-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol),Pd(dppf)Cl₂ (52 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The air in the mixture was removed by bubbling with nitrogen for 10 minand the mixture was stirred at 110° C. for 3 h. The mixture was filteredthrough a celite pad, and the filter cake was washed with ethyl acetate(50 mL). The filtrate was washed with saturated brine (50 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=5/1) to give the title compound asa yellow solid (120 mg, 65%).

MS (ESI, pos. ion) m/z: 582.1[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.25 (d, J=9.4 Hz, 2H), 8.10 (dd,J=11.7, 5.7 Hz, 3H), 7.30 (s, 1H), 5.19 (d, J=5.5 Hz, 1H), 4.68 (s, 1H),3.52 (s, 3H), 2.62 (d, J=1.9 Hz, 3H), 2.45 (d, J=5.5 Hz, 1H), 2.39 (s,3H), 2.04 (s, 1H), 1.95 (s, 2H), 1.87-1.62 (m, 8H).

Step 8:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(120 mg, 0.21 mmol) in THF/MeOH (v/v=1/1, 4 mL) was added aqueous sodiumhydroxide solution (4 M, 0.53 mL, 2.10 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine, dried overanhydrous sodium sulfate, then filtered. The filtrate was concentratedin vacuo to remove the solvent and the residue was purified by silicagel column chromatography (DCM/MeOH (v/v)=10/1) to give the titlecompound as a yellow solid (32 mg, 38%).

MS (ESI, pos. ion) m/z: 414.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 414.1750 [M+H]⁺, (C₂₁H₂₂F2N₅O₂)[M+H]⁺theoretical value: 414.1742;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.31 (s, 1H), 12.07 (s, 1H), 8.55(s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.10 (s, 2H), 7.60-7.38 (m, 4H), 6.76(s, 1H), 4.64 (s, 1H), 2.53 (d, J=2.5 Hz, 4H), 1.99 (s, 2H), 1.86-1.39(m, 8H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 175.93, 167.43, 158.37, 158.31,156.07, 153.72, 151.71, 151.60, 146.15, 138.48, 138.31, 132.21, 132.02,131.80, 131.45, 131.14, 129.11, 126.98, 126.81, 117.69, 67.90, 50.33,48.21, 38.59, 30.28, 29.08, 28.83, 28.74, 25.74, 24.27, 23.74, 22.84,21.48, 19.43, 14.32, 13.61, 13.56, 11.25.

Example 46:(+/−)-trans-3-((2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2.2]octane-2-carboxylate

To a sealed tube were added5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(112 mg, 0.26 mmol), (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(80 mg, 0.22 mmol), potassium carbonate (89 mg, 0.65 mmol), Pd(dppf)Cl₂(35 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min and themixture was stirred at 110° C. for 3 h. The mixture was filtered througha celite pad, and the filter cake was washed with ethyl acetate (50 mL).The filtrate was washed with saturated brine (50 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(92 mg, 67%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.37 (s, 1H), 8.26 (s, 1H), 8.12 (d,J=8.3 Hz, 2H), 8.07 (d, J=5.6 Hz, 2H), 7.54-7.46 (m, 3H), 7.30 (s, 1H),6.83 (s, 1H), 5.29 (s, 1H), 4.46 (s, 1H), 3.69 (s, 3H), 2.67 (s, 3H),2.46 (d, J=5.1 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 1H), 1.96-1.94 (m, 1H),1.71 (m, 8H).

Step 2:(+/−)-trans-3-((2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(92 mg, 0.14 mmol) in THF/MeOH (v/v=1/1, 4 mL) was added aqueous sodiumhydroxide solution (4 M, 0.33 mL, 1.40 mmol). The mixture was stirred at30° C. overnight. To the reaction mixture was added water (10 mL), andthe resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 5.5. The mixture was extracted with ethyl acetate (20 mL×3), andthe combined organic layers were washed with saturated brine (50 mL),dried over anhydrous sodium sulfate, then filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give thetitle compound as a yellow solid (49 mg, 72%).

MS (ESI, pos. ion) m/z: 472.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 472.2147 [M+H]⁺, (C₂₇H₂₇FN₅O₂)[M+H]⁺theoretical value: 472.2149;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 8.18 (s, 1H), 8.14 (s,1H), 8.04 (s, 2H), 7.51 (d, J=7.6 Hz, 4H), 6.81 (s, 1H), 4.61 (s, 1H),2.84 (s, 3H), 1.96 (s, 1H), 1.83-1.39 (m, 10H).

Example 47:(+/−)-trans-3-((2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tube were added5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(91 mg, 0.21 mmol), (+/−)-trans-methyl3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(60 mg, 0.17 mmol), potassium carbonate (71 mg, 0.51 mmol), Pd(dppf)Cl₂(28 mg, 0.03 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min and themixture was stirred at 110° C. for 4 h. The mixture was filtered througha celite pad, and the filter cake was washed with ethyl acetate (50 mL).The filtrate was washed with saturated brine (50 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(77 mg, 73%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.32 (s, 1H), 8.24 (s, 1H), 8.13 (d,J=8.2 Hz, 2H), 6.96 (d, J=3.4 Hz, 1H), 6.45 (s, 1H), 5.18 (s, 1H), 4.78(s, 1H), 3.82 (s, 3H), 3.77 (s, 1H), 3.54 (s, 3H), 2.68 (s, 3H), 2.47(d, J=5.1 Hz, 1H), 2.39 (s, 3H), 2.03 (s, 2H), 1.90-1.62 (m, 8H).

Step 2:(+/−)-trans-3-((2-(5-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-4-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(75 mg, 0.12 mmol) in THF/MeOH (v/v=1/1, 4 mL) was added a solution ofsodium hydroxide in water (4 M, 0.30 mL, 1.20 mmol). The mixture wasstirred at 30° C. overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 5.5. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1)to give the title compound as a yellow solid (19 mg, 35%).

MS (ESI, pos. ion) m/z: 449.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 449.2115 [M+H]⁺, (C₂₄H₂₆FN₆O₂)[M+H]⁺theoretical value: 449.2101;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.09 (s, 1H), 8.26-8.07 (m, 2H),7.96 (d, J=2.1 Hz, 1H), 7.78-7.59 (m, 1H), 7.50 (d, J=6.8 Hz, 1H), 4.64(s, 1H), 4.14 (s, 1H), 2.79 (s, 4H), 1.97 (s, 1H), 1.63 (m, 8H).

Example 48:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a reaction flask were added 2,4,6-trichloro-5-fluoropyrimidine (10.00g, 49.65 mmol), potassium carbonate (21.00 g, 148.90 mmol),(+/−)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (10.00 g,54.61 mmol) and DMF (50 mL). The mixture was stirred at rt for 5 h. Whenthe reaction was completed, to the reaction mixture was added water (100mL), and the resulting mixture was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as alight yellow solid (12.00 g, 69%).

MS (ESI, pos. ion) m/z: 348.10[M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (100 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(2.00 g, 5.74 mmol), phenylboronic acid (0.70 g, 5.74 mmol), potassiumacetate (1.70 g, 17.2 mmol) and Pd(dppf)Cl₂ (0.50 g, 0.57 mmol), then tothe mixture was added water (5 mL). The resulting mixture was stirred at80° C. for 12 h under nitrogen protection. The mixture was filtered toremove solid impurities. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a yellow solid (430 mg, 19%).

MS (ESI, pos. ion) m/z: 390.1[M+H]⁺.

Step 3: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(670 mg, 0.97 mmol, 60%), potassium carbonate (570 mg, 4.10 mmol),palladium acetate (23 mg, 0.10 mmol), X-Phos (100 mg, 0.20 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(400 mg, 1.02 mmol). Then H₂O (1 mL) was added to the mixture, and themixture was heated to 110° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(200 mg, 30%).

MS (ESI, pos. ion) m/z: 644.3[M+H]⁺.

Step 4:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.31 mmol) in a mixed solvent of THF (8 mL) and MeOH (4 mL) wasadded a solution of NaOH (124 mg, 3.10 mmol) in water (2 mL). Themixture was stirred at rt overnight, then diluted with water (10 mL).The resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 3 to 4. The resulting mixture was extracted with ethyl acetate (20mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to givethe title compound as a white solid (100 mg, 68%).

MS (ESI, pos. ion) m/z: 476.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 476.1816 [M+H]⁺, (C₂₆H₂₄F2N₅O₂)[M+H]⁺theoretical value: 476.1898;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.52 (s, 1H), 12.26 (s, 1H), 8.68(d, J=8.0 Hz, 1H), 8.37 (d, J=7.6 Hz, 3H), 8.25 (s, 1H), 7.53 (m, 4H),4.70 (s, 1H), 3.58 (s, 2H), 2.89 (d, J=6.2 Hz, 1H), 2.17 (s, 1H), 2.01(s, 1H), 1.95 (s, 1H), 1.50 (m, 5H).

Example 49:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (100 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(2.00 g, 5.74 mmol), 2-furanboronic acid (0.65 g, 5.74 mmol), potassiumacetate (1.70 g, 17.2 mmol) and Pd(dppf)Cl₂ (0.50 g, 0.57 mmol), then tothe mixture was added water (5 mL). The resulting mixture was stirred at80° C. for 12 h under nitrogen protection. The mixture was filtered toremove solid impurities. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a yellow solid (700 mg, 30%).

MS (ESI, pos. ion) m/z: 380.2[M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(390 mg, 0.55 mmol, 60%), potassium carbonate (290 mg, 2.10 mmol),palladium acetate (11 mg, 0.05 mmol), X-Phos (50 mg, 0.10 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 1.02 mmol). Then H₂O (1 mL) was added to the mixture, and themixture was heated to 100° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(250 mg, 75%).

MS (ESI, pos. ion) m/z: 634.2 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(250 mg, 0.40 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (140 mg, 4.00 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (120 mg, 54%).

MS (ESI, pos. ion) m/z: 466.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 466.1699 [M+H]⁺, (C₂₄H₂₂F2N₅O₃S) [M+H]⁺theoretical value: 466.1691;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.60 (d, J=8.4 Hz,1H), 8.27 (d, J=8.8 Hz, 2H), 8.00 (s, 1H), 7.61 (d, J=5.8 Hz, 1H), 7.24(s, 1H), 6.75 (s, 1H), 4.71 (s, 1H), 2.88 (d, J=5.5 Hz, 1H), 2.01 (s,1H), 1.98 (s, 1H), 1.77 (m, 3H), 1.50 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.04, 157.58, 157.32, 154.93,152.60, 148.55, 146.40, 145.65, 140.32, 137.72, 137.24, 131.91, 131.62,131.24, 118.82, 115.48, 114.30, 112.64, 51.14, 48.29, 40.40, 40.20,39.99, 39.78.

Example 50:(+/−)-trans-3-((6-([1,1′-biphenyl]-4-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((6-([1,1′-biphenyl]-4-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (50 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(1.00 g, 2.87 mmol), [1,1′-biphenyl]-4-ylboronic acid (0.57 g, 2.87mmol), potassium acetate (0.85 g, 8.62 mmol) and Pd(dppf)Cl₂ (0.25 g,0.28 mmol), then to the mixture was added water (2 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (600 mg, 45%).

MS (ESI, pos. ion) m/z: 466.0 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-([1,1′-biphenyl]-4-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(450 mg, 0.64 mmol, 60%), potassium carbonate (355 mg, 2.57 mmol),palladium acetate (14 mg, 0.06 mmol), X-Phos (61 mg, 0.12 mmol) and(+/−)-trans-methyl3-((6-([1,1′-biphenyl]-4-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate(300 mg, 0.64 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(300 mg, 65%).

MS (ESI, pos. ion) m/z: 720.1 [M+H]⁺.

Step 3:(+/−)-trans-3-((6-([1,1′-biphenyl]-4-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((6-([1,1′-biphenyl]-4-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(300 mg, 0.42 mmol) in a mixed solvent of THF (8 mL) and MeOH (4 mL) wasadded a solution of NaOH (184 mg, 4.20 mmol) in water (2 mL). Themixture was stirred at rt overnight, then diluted with water (10 mL).The resulting mixture was acidified with hydrochloric acid (1 M) to pHabout 3 to 4. The resulting mixture was extracted with ethyl acetate (20mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to givethe title compound as a white solid (103 mg, 45%).

MS (ESI, pos. ion) m/z: 552.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 552.2221 [M+H]⁺, (C₃₂H₂₈F2N₅O₅₂) [M+H]⁺theoretical value: 552.2211;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.31 (s, 1H), 8.58 (d, J=7.7 Hz,1H), 8.31 (d, J=10.0 Hz, 2H), 8.18 (d, J=7.9 Hz, 2H), 7.88 (d, J=8.1 Hz,2H), 7.78 (d, J=7.5 Hz, 2H), 7.65 (d, J=5.9 Hz, 1H), 7.51 (t, J=7.4 Hz,2H), 7.41 (t, J=7.1 Hz, 1H), 4.76 (s, 1H), 2.93 (d, J=6.0 Hz, 1H), 2.03(s, 2H), 1.90-1.74 (m, 3H), 1.52 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.07, 157.52, 157.43, 157.30,154.91, 152.99, 152.86, 151.95, 146.43, 144.74, 144.68, 142.89, 141.88,140.31, 139.87, 139.62, 133.69, 133.64, 131.90, 131.61, 131.30, 130.06,129.60, 129.54, 129.48, 128.35, 127.24, 125.35, 118.86, 118.79, 115.55,115.33, 114.42, 114.38, 40.44, 40.23, 40.02, 39.81, 39.60, 30.89.

Example 51:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (0.18 g,1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13g, 0.14 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove the solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (190 mg, 34%).

MS (ESI, pos. ion) m/z: 394.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(422 mg, 0.61 mmol, 60%), potassium carbonate (280 mg, 2.03 mmol),palladium acetate (22 mg, 0.10 mmol), X-Phos (100 mg, 0.20 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.51 mmol). Then H₂O (0.5mL) was added to the mixture, and the mixture was heated to 80° C. andstirred for 12 h. The mixture was filtered to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the titlecompound as a light yellow solid (280 mg, 85%).

MS (ESI, pos. ion) m/z: 648.3 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(280 mg, 0.43 mmol) in a mixed solvent of THF (8 mL) and MeOH (4 mL) wasadded a solution of NaOH (172 mg, 4.30 mmol) in water (2 mL). Themixture was stirred at rt overnight, then water (10 mL) was added. Theresulting mixture was acidified with hydrochloric acid (1 M) to pH about3 to 4. The resulting mixture was extracted with ethyl acetate (20mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to givethe title compound as a white solid (180 mg, 87%).

MS (ESI, pos. ion) m/z: 480.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 480.1964 [M+H]⁺, (C₂₄H₂₄F₂N₇O₂)[M+H]⁺theoretical value: 480.1960;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.26 (s, 1H), 8.56 (dd, J=9.6, 2.4Hz, 1H), 8.39 (s, 1H), 8.35-8.25 (m, 2H), 8.10 (s, 1H), 7.48 (d, J=6.5Hz, 1H), 4.71 (s, 1H), 3.97 (s, 3H), 2.89 (d, J=6.5 Hz, 1H), 2.01 (d,J=10.8 Hz, 2H), 1.79 (m, 3H), 1.56 (m, 4H), 1.19 (s, 2H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.06, 157.51, 154.90, 152.16,146.40, 140.65, 139.00, 131.99, 131.79, 131.27, 130.04, 125.35, 118.75,116.78, 115.61, 115.40, 114.45, 51.00, 40.42, 40.21, 40.00, 39.79,39.58, 28.84.

Example 52:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), p-methoxyphenylboronic acid (0.22 g, 1.44 mmol),potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g, 0.14mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (200 mg, 33%).

MS (ESI, pos. ion) m/z: 420.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(363 mg, 0.52 mmol, 60%), potassium carbonate (263 mg, 1.90 mmol),palladium acetate (21 mg, 0.09 mmol), X-Phos (100 mg, 0.20 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.47 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(230 mg, 72%).

MS (ESI, pos. ion) m/z: 674.2 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(230 mg, 0.34 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (136 mg, 3.40 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (130 mg, 75%).

MS (ESI, pos. ion) m/z: 506.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 506.2014 [M+H]⁺, (C₂₇H₂₆F2N₅O₃)[M+H]⁺theoretical value: 506.2004;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.55 (d, J=8.6 Hz,1H), 8.30 (s, 2H), 8.07 (d, J=7.8 Hz, 2H), 7.54 (d, J=5.1 Hz, 1H), 7.13(d, J=8.0 Hz, 2H), 4.73 (s, 1H), 3.85 (s, 3H), 2.90 (d, J=5.0 Hz, 1H),2.02 (s, 2H), 1.80 (d, J=9.9 Hz, 3H), 1.70-1.42 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.06, 161.00, 157.22, 154.89,152.91, 152.81, 151.92, 146.41, 139.61, 131.84, 131.55, 131.19, 130.56,130.50, 128.48, 126.89, 125.35, 118.86, 115.53, 114.48, 55.74, 40.42,40.22, 40.01, 39.80, 39.59, 30.88.

Example 53:(+/−)-trans-3-((6-(4-(tert-butyl)phenyl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((6-(4-(tert-butyl)phenyl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), (4-(tert-butyl)phenyl)boronic acid (0.26 g, 1.44mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g,0.14 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (180 mg, 28%).

MS (ESI, pos. ion) m/z: 446.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(4-(tert-butyl)phenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrol[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(308 mg, 0.44 mmol, 60%), potassium carbonate (223 mg, 1.61 mmol),palladium acetate (18 mg, 0.08 mmol), X-Phos (76 mg, 0.16 mmol) and(+/−)-trans-methyl3-((6-(4-(tert-butyl)phenyl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(180 mg, 0.40 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. under nitrogen protection and stirred for12 h. The mixture was filtered to remove solid impurities. The filtratewas concentrated in vacuo, and the residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=8/1) to give the title compound asa light yellow solid (110 mg, 39%).

Step 3:(+/−)-trans-3-((6-(4-(tert-butyl)phenyl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((6-(4-(tert-butyl)phenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(110 mg, 0.16 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (62 mg, 1.60 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (51 mg, 61%).

MS (ESI, pos. ion) m/z: 532.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 532.2523 [M+H]⁺, (C₃₀H₃₂F₂N₅O₂) [M+H]⁺theoretical value: 532.2524;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.52 (s, 1H), 12.27 (s, 1H), 8.70(dd, J=9.7, 2.5 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J=8.2 Hz, 2H), 8.24 (s,1H), 7.58 (d, J=8.3 Hz, 2H), 7.54 (d, J=6.6 Hz, 1H), 4.69 (t, J=6.6 Hz,1H), 2.88 (d, J=6.9 Hz, 1H), 2.01 (s, 1H), 1.95 (s, 1H), 1.84-1.72 (m,3H), 1.64-1.40 (m, 5H), 1.34 (s, 9H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.11, 158.23, 155.11, 153.03,151.94, 145.84, 139.65, 135.85, 133.10, 132.59, 132.40, 132.14, 132.03,128.49, 127.75, 125.81, 125.37, 118.81, 116.27, 108.31, 50.90, 48.00,40.24, 40.10, 39.96, 39.82, 39.68, 34.84, 31.52, 30.88.

Example 54:(+/−)-trans-3-((6-(benzofuran-2-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), benzofuran-2-ylboronic acid (0.23 g, 1.44 mmol),potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g, 0.14mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (230 mg, 37%).

MS (ESI, pos. ion) m/z: 430.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(445 mg, 0.64 mmol, 60%), potassium carbonate (300 mg, 2.14 mmol),palladium acetate (24 mg, 0.10 mmol), X-Phos (102 mg, 0.20 mmol) and(+/−)-trans-methyl3-((6-(benzofuran-2-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(230 mg, 0.54 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 110° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo to remove solvent, and the residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=8/1) to give the title compound asa light yellow solid (180 mg, 49%).

Step 3:(+/−)-trans-3-((6-(benzofuran-2-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-(benzofuran-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(180 mg, 0.26 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (105 mg, 2.63 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1−5/1) to give the title compound as a white solid (91 mg,67%).

MS (ESI, pos. ion) m/z: 516.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 516.1845 [M+H]⁺, (C₂₈H₂₄F2N₅O₃)[M+H]⁺theoretical value: 516.1847;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.35 (s, 1H), 8.62 (dd, J=9.7, 2.5Hz, 1H), 8.38-8.29 (m, 2H), 7.84 (d, J=7.7 Hz, 1H), 7.80 (d, J=6.5 Hz,1H), 7.78-7.72 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.36 (t, J=7.4 Hz, 1H),4.74 (s, 1H), 2.92 (d, J=6.4 Hz, 1H), 2.06-1.98 (m, 2H), 1.80 (m, 3H),1.64-1.36 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.04, 155.35, 155.09, 152.73,151.93, 150.50, 146.40, 139.64, 131.50, 128.49, 128.24, 126.63, 125.37,124.03, 122.68, 118.85, 118.80, 115.64, 115.50, 112.08, 110.33, 110.27,40.24, 40.10, 39.96, 39.82, 39.68, 30.87.

Example 55:(+/−)-trans-3-((6-(benzo[b]thiophen-2-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), benzo[b]thiophen-2-ylboronic acid (0.25 g, 1.44mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g,0.14 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (300 mg, 47%).

MS (ESI, pos. ion) m/z: 446.0 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(513 mg, 0.74 mmol, 60%), potassium carbonate (371 mg, 2.69 mmol),palladium acetate (30 mg, 0.13 mmol), X-Phos (128 mg, 0.26 mmol) and(+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (300 mg, 0.67 mmol). Then H₂O (0.5mL) was added to the mixture, and the mixture was heated to 80° C. andstirred for 12 h. The mixture was filtered to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the titlecompound as a light yellow solid (200 mg, 42%).

Step 3:(+/−)-trans-3-((6-(benzo[b]thiophen-2-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((6-(benzo[b]thiophen-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.28 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (114 mg, 2.80 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (91 mg, 60%).

MS (ESI, pos. ion) m/z: 532.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 532.1608[M+H]⁺, (C₂₈H₂₄F2N₅O₂S)[M+H]⁺theoretical value: 532.1619;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.34 (s, 1H), 8.63 (dd, J=9.6, 2.4Hz, 1H), 8.32 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 8.13-8.08(m, 1H), 8.05-8.00 (m, 1H), 7.77 (d, J=6.4 Hz, 1H), 7.49-7.43 (m, 2H),4.72 (s, 1H), 2.90 (d, J=6.4 Hz, 1H), 2.02 (d, J=9.4 Hz, 2H), 1.87-1.75(m, 3H), 1.65-1.42 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.07, 155.37, 151.94, 146.43,140.73, 139.65, 131.47, 128.50, 126.35, 125.37, 125.27, 123.00, 119.13,118.75, 118.72, 118.70, 115.54, 115.47, 115.40, 114.32, 113.87, 113.84,40.25, 40.11, 39.97, 39.83, 39.69, 30.88.

Example 56:(+/−)-trans-3-((6-(4-cyanophenyl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-6-(4-cyanophenyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), (4-cyanophenyl)boronic acid (0.22 g, 1.44 mmol),potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g, 0.14mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (250 mg, 42%).

MS (ESI, pos. ion) m/z: 415.1 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(4-cyanophenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(460 mg, 0.66 mmol, 60%), potassium carbonate (333 mg, 2.41 mmol),palladium acetate (27 mg, 0.12 mmol), X-Phos (114 mg, 0.24 mmol) and(+/−)-trans-methyl3-((2-chloro-6-(4-cyanophenyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(250 mg, 0.60 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(250 mg, 62%).

Step 3:(+/−)-trans-3-((6-(4-cyanophenyl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-(4-cyanophenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(250 mg, 0.37 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (149 mg, 3.70 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid topH about 3 to 4. The mixture was extracted with ethyl acetate (20 mL×3),and the combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, then filtered. The filtratewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=10/1−5/1) to give the titlecompound as a white solid (120 mg, 64%).

MS (ESI, pos. ion) m/z: 501.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 501.1846 [M+H]⁺, (C₂₇H₂₃F₂N₆O₂)[M+H]⁺theoretical value: 501.1851;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.31 (s, 1H), 8.50 (dd, J=9.5, 2.2Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J=8.1 Hz, 2H),8.02 (d, J=8.2 Hz, 2H), 7.76 (d, J=6.2 Hz, 1H), 4.75 (s, 1H), 2.92 (d,J=6.2 Hz, 1H), 2.02 (d, J=11.4 Hz, 2H), 1.80 (m, 3H), 1.69-1.40 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ(ppm): 176.05, 157.69, 157.64, 156.89,155.29, 153.00, 152.92, 151.93, 146.38, 140.98, 139.64, 139.06, 139.03,132.96, 131.72, 131.55, 129.83, 129.79, 128.49, 125.37, 119.09, 112.65,40.24, 40.10, 39.96, 39.82, 39.68, 30.87.

Example 57:(+/−)-trans-3-((6-(3,4-difluorophenyl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-6-(3,4-difluorophenyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), (3,4-difluorophenyl)boronic acid (0.23 g, 1.44mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g,0.14 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (290 mg, 47%).

MS (ESI, pos. ion) m/z: 426.1 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(3,4-difluorophenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrol[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(520 mg, 0.74 mmol, 60%), potassium carbonate (376 mg, 2.72 mmol),palladium acetate (30 mg, 0.14 mmol), X-Phos (130 mg, 0.28 mmol) and(+/−)-trans-methyl3-((2-chloro-6-(3,4-difluorophenyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(290 mg, 0.68 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(240 mg, 52%).

MS (ESI, pos. ion) m/z: 680.1 [M+H]⁺.

Step 3:(+/−)-trans-3-((6-(3,4-difluorophenyl)-5-fluoro-2-(5-fluoro-H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((6-(3,4-difluorophenyl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(240 mg, 0.35 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (141 mg, 3.40 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (97 mg, 54%).

MS (ESI, pos. ion) m/z: 512.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 512.1699 [M+H]⁺, (C₂₆H₂₂F₄N₅O₂)[M+H]⁺theoretical value: 512.1710;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.30 (s, 1H), 8.51 (dd, J=9.7, 2.5Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 8.28 (s, 1H), 8.10 (dd, J=10.1, 8.5 Hz,1H), 7.93 (s, 1H), 7.70 (d, J=6.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 4.74(t, J=6.1 Hz, 1H), 2.92 (d, J=6.6 Hz, 1H), 2.02 (d, J=12.5 Hz, 2H),1.87-1.73 (m, 3H), 1.69-1.40 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.04, 158.28, 157.52, 157.46,157.03, 156.88, 155.29, 152.99, 152.90, 151.93, 146.39, 140.60, 139.64,131.63, 128.49, 126.29, 125.36, 118.72, 118.29, 118.17, 114.11, 40.23,40.09, 39.95, 39.81, 39.68, 30.86.

Example 58:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile were added(+/−)-trans-methyl-3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), furan-3-ylboronic acid (0.16 g, 1.44 mmol),potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g, 0.14mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (140 mg, 30%).

MS (ESI, pos. ion) m/z: 380.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(442 mg, 0.63 mmol, 60%), potassium carbonate (203 mg, 1.46 mmol),palladium acetate (16 mg, 0.07 mmol), X-Phos (70 mg, 0.14 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(140 mg, 0.36 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(198 mg, 85%).

MS (ESI, pos. ion) m/z: 634.2 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(198 mg, 0.31 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (125 mg, 3.10 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (130 mg, 89%).

MS (ESI, pos. ion) m/z: 466.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 466.1689 [M+H]⁺, (C₂₄H₂₂F₂N₅O₃)[M+H]⁺theoretical value: 466.1691;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 8.54 (dd, J=9.6, 2.1Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.29 (s, 1H), 7.89 (s,1H), 7.57 (d, J=6.4 Hz, 1H), 7.16 (s, 1H), 4.72 (s, 1H), 2.89 (d, J=6.4Hz, 1H), 2.00 (d, J=12.4 Hz, 2H), 1.79 (m, 3H), 1.51 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.07, 157.61, 156.88, 155.29,152.23, 151.93, 146.39, 144.92, 144.61, 139.64, 131.47, 128.50, 125.37,121.30, 118.72, 115.52, 114.24, 109.92, 55.36, 51.03, 48.15, 34.83,30.87, 28.81.

Example 59:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.27 g,1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13g, 0.14 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (230 mg, 45%).

MS (ESI, pos. ion) m/z: 458.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(383 mg, 0.55 mmol, 60%), potassium carbonate (277 mg, 2.01 mmol),palladium acetate (22 mg, 0.10 mmol), X-Phos (95 mg, 0.20 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (230 mg, 0.50 mmol). Then H₂O (0.5mL) was added to the mixture, and the mixture was heated to 80° C. andstirred for 12 h. The mixture was filtered to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the titlecompound as a light yellow solid (180 mg, 50%).

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(180 mg, 0.25 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (101 mg, 2.50 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1−5/1) to give the title compound as a white solid (90 mg,65%).

MS (ESI, pos. ion) m/z: 544.3 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 544.1770 [M+H]⁺, (C₂₆H₂₄F₂N₅O₂)[M+H]⁺theoretical value: 544.1772;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.54 (s, 1H), 8.60 (d, J=8.0 Hz,1H), 8.51 (d, J=7.9 Hz, 2H), 8.35 (s, 1H), 8.24 (s, 1H), 7.91 (d, J=8.0Hz, 2H), 7.66 (d, J=6.1 Hz, 1H), 4.68 (s, 1H), 2.87 (d, J=6.2 Hz, 1H),2.00 (s, 1H), 1.93 (s, 1H), 1.76 (m, 3H), 1.49 (m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 176.12, 156.79, 155.12, 152.12,145.84, 143.49, 142.22, 142.02, 140.30, 132.67, 132.47, 132.37, 132.27,130.27, 126.04, 125.88, 124.21, 118.69, 116.05, 108.45, 51.04, 48.07,28.81, 25.82, 24.30, 21.58.

Example 60:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added(+/−)-trans-methyl-3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.50 g, 1.44 mmol), p-methylphenylboronic acid (0.20 g, 1.44 mmol),potassium acetate (0.42 g, 4.31 mmol) and Pd(dppf)Cl₂ (0.13 g, 0.14mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo to remove solvent, and the residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=20/1) to give the title compoundas a yellow solid (300 mg, 52%).

MS (ESI, pos. ion) m/z: 404.2 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(550 mg, 0.81 mmol, 60%), potassium carbonate (410 mg, 2.97 mmol),palladium acetate (33 mg, 0.14 mmol), X-Phos (141 mg, 0.28 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(300 mg, 0.74 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove the solid impurity. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(300 mg, 61%).

MS (ESI, pos. ion) m/z: 658.1 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(p-tolyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(300 mg, 0.45 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (182 mg, 4.50 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (140 mg, 63%).

MS (ESI, pos. ion) m/z: 490.3[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 490.2053 [M+H]⁺, (C₂₇H₂₆F₂N₅O₂)[M+H]⁺theoretical value: 490.2055;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1H), 8.56 (d, J=8.6 Hz,1H), 8.29 (s, 2H), 7.97 (d, J=7.4 Hz, 2H), 7.56 (d, J=5.6 Hz, 1H), 7.36(d, J=7.6 Hz, 2H), 4.74 (s, 1H), 2.91 (d, J=5.6 Hz, 1H), 2.00 (d, J=15.6Hz, 2H), 1.88-1.73 (m, 3H), 1.53 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.06, 157.33, 154.90, 152.94,151.93, 146.42, 145.13, 142.66, 139.98, 139.59, 131.84, 131.19, 129.59,128.92, 128.86, 125.34, 118.88, 118.81, 115.56, 115.34, 114.42, 51.17,48.26, 34.80, 30.86, 28.84, 21.39, 19.50.

Example 61:(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid

Step 1: (R)-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To a reaction flask were added 2,4,6-trichloro-5-fluoropyrimidine (0.64g, 3.16 mmol), DIPEA (1.02 g, 7.91 mmol), (R)-methyl3-amino-4,4-dimethylpentanoate (0.42 g, 2.63 mmol) and dichloromethane(10 mL). The mixture was stirred at rt for 24 h. After the reaction wascompleted, to the mixture was added water (20 mL). The resulting mixturewas extracted with DCM (20 mL). The organic layer was washed withsaturated brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel chromatography eluted withPE/EtOAc (v/v=20/1) to give the title compound as a light yellow solid(420 mg, 49%).

MS (ESI, pos. ion) m/z: 324.10 [M+H]⁺.

Step 2: (R)-methyl3-((2-chloro-5-fluoro-6-(furan-2-yl)pyrimidin-4-yl)amino)4,4-dimethylpentanoate

To acetonitrile (25 mL) were added (R)-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate(420 mg, 1.29 mmol), furan-2-ylboronic acid (145 mg, 1.29 mmol),potassium acetate (381 mg, 3.88 mmol) and Pd(dppf)Cl₂ (105 mg, 0.13mmol), then to the mixture was added water (1 mL). The resulting mixturewas stirred at 80° C. for 12 h under nitrogen protection. The mixturewas filtered to remove solid impurities. The filtrate was concentratedin vacuo to remove the solvent, and the residue was purified by silicagel column chromatography (PE/EtOAc (v/v)=20/1) to give the titlecompound as a yellow solid (180 mg, 39%).

MS (ESI, pos. ion) m/z: 356.2 [M+H]⁺.

Step 3: (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(386 mg, 0.56 mmol, 60%), potassium carbonate (280 mg, 2.02 mmol),palladium acetate (22 mg, 0.10 mmol), X-Phos (100 mg, 0.20 mmol) and(R)-methyl3-((2-chloro-5-fluoro-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoatee(180 mg, 0.50 mmol). Then H₂O (1 mL) was added to the mixture, and themixture was heated to 100° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(230 mg, 74%).

MS (ESI, pos. ion) m/z: 610.2 [M+H]⁺.

Step 4:(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

To a solution of (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(230 mg, 0.37 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (150 mg, 3.70 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (20mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1−5/1) to give the title compound as a white solid (110 mg,66%).

MS (ESI, pos. ion) m/z: 442.3[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 442.1687 [M+H]⁺, (C₂₂H₂₂F₂N₅O₃)[M+H]⁺theoretical value: 442.1691;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.26 (s, 1H), 12.05 (s, 1H), 8.65(d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.45 (d,J=8.7 Hz, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 4.84 (t, J=8.4 Hz, 1H),2.73-2.56 (m, 2H), 0.99 (s, 9H).

Example 62:(+/−)-trans-3-((6-(dibenzo[b,d]furan-4-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-6-(dibenzo[b,d]furan-4-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.40 g, 1.15 mmol), dibenzo[b,d]furan-4-ylboronic acid (0.244 g, 1.15mmol), potassium acetate (0.33 g, 3.45 mmol) and Pd(dppf)Cl₂ (0.09 g,0.11 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (170 mg, 31%).

MS (ESI, pos. ion) m/z: 480.1 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((6-(dibenzo[b,d]furan-4-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(286 mg, 0.41 mmol, 60%), potassium carbonate (207 mg, 1.50 mmol),palladium acetate (16 mg, 0.07 mmol), X-Phos (71 mg, 0.14 mmol) and(+/−)-trans-methyl3-((2-chloro-6-(dibenzo[b,d]furan-4-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (180 mg, 0.37 mmol). Then H₂O (0.5mL) was added to the mixture, and the mixture was heated to 80° C. andstirred for 12 h. The mixture was filtered to remove the solidimpurities. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=8/1) togive the title compound as a light yellow solid (200 mg, 73%).

MS (ESI, pos. ion) m/z: 734.1[M+H]⁺.

Step 3:(+/−)-trans-3-((6-(dibenzo[b,d]furan-4-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((6-(dibenzo[b,d]furan-4-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.27 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (109 mg, 2.72 mmol) in water (1 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=10/1−5/1) to give thetitle compound as a white solid (130 mg, 84%).

MS (ESI, pos. ion) m/z: 566.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 566.1982 [M+H]⁺, (C₃₂H₂₆F₂N₅O₃)[M+H]⁺theoretical value: 566.2004;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.30 (s, 1H), 8.61 (d, J=8.3 Hz,1H), 8.29 (s, 3H), 8.22 (d, J=6.5 Hz, 1H), 7.91 (d, J=6.3 Hz, 1H), 7.80(s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.64-7.51 (m, 2H), 7.44 (s, 1H), 4.80(s, 1H), 2.93 (s, 1H), 2.06 (s, 2H), 1.65 (m, 8H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.08, 157.96, 157.88, 156.03,154.95, 153.30, 152.53, 152.41, 151.93, 146.43, 143.29, 143.18, 140.09,139.61, 131.96, 131.67, 131.26, 128.61, 128.48, 128.43, 125.35, 124.73,123.76, 122.95, 121.77, 119.62, 118.95, 118.87, 115.68, 115.46, 114.33,112.13, 51.22, 48.25, 34.80, 30.87, 28.83, 28.75, 22.30, 22.04.

Example 63:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 2,4-dichloro-5-fluoro-6-(phenylethynyl)pyrimidine

To THF (20 mL) were added 2,4,6-trichloro-5-fluoropyrimidine (1.00 g,4.96 mmol), cuprous iodide (0.19 g, 9.92 mmol),bis(triphenylphosphine)palladium(II) chloride (0.35 g, 0.49 mmol) andtriethylamine (1.51 g, 14.9 mmol). Then to the mixture was addeddropwise slowly phenylacetylene (0.48 g, 4.70 mmol) under nitrogenprotection, and the mixture was stirred at rt for 4 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE) to give the title compound as a yellow solid (550 mg, 42%).

MS (ESI, pos. ion) m/z: 266.9 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a reaction flask were added2,4-dichloro-5-fluoro-6-(phenylethynyl)pyrimidine (0.55 g, 2.05 mmol),DIPEA (0.53 g, 4.11 mmol), (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (0.46 g, 2.47 mmol) and DCM(10 mL). The mixture was stirred at rt for 18 h. After the reaction wascompleted, to the reaction mixture was added water (20 mL), and theresulting mixture was extracted with DCM (20 mL×3). The combined organiclayers were washed with saturated brine (10 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=8/1) to give the title compound as a light yellow solid (0.58 g,68%).

MS (ESI, pos. ion) m/z: 414.3[M+H]⁺.

Step 3: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(400 mg, 0.58 mmol, 60%), potassium carbonate (267 mg, 1.93 mmol),palladium acetate (21 mg, 0.09 mmol), X-Phos (92 mg, 0.18 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.48 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(162 mg, 50%).

Step 4:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(162 mg, 0.24 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (97 mg, 2.40 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1-5/1) to give the title compound as a white solid (99 mg,82%).

MS (ESI, pos. ion) m/z: 500.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 500.1892 [M+H]⁺, (C₂₈H₂₄F₂N₅O₂)[M+H]⁺theoretical value: 500.1898;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.32 (s, 1H), 8.51 (dd, J=9.6, 2.2Hz, 1H), 8.31-8.25 (m, 2H), 7.80 (d, J=6.6 Hz, 1H), 7.70-7.64 (m, 2H),7.50 (d, J=6.7 Hz, 3H), 4.74 (s, 1H), 2.90 (d, J=6.4 Hz, 1H), 2.03 (s,1H), 1.98 (s, 1H), 1.80 (m, 3H), 1.69-1.41 (m, 5H).

Example 64:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To acetonitrile (25 mL) were added (+/−)-trans-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(0.40 g, 1.14 mmol), (1-methyl-1H-pyrrol-3-yl)boronic acid (0.23 g, 1.14mmol), potassium acetate (0.34 g, 3.46 mmol) and Pd(dppf)Cl₂ (0.09 g,0.11 mmol), then to the mixture was added water (1 mL). The resultingmixture was stirred at 80° C. for 12 h under nitrogen protection. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound as ayellow solid (150 mg, 33%).

MS (ESI, pos. ion) m/z: 393.1 [M+H]⁺.

Step 2: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(423 mg, 0.46 mmol, 45%), potassium carbonate (211 mg, 1.52 mmol),palladium acetate (17 mg, 0.07 mmol), X-Phos (72 mg, 0.14 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (150 mg, 0.38 mmol). Then H₂O (0.5mL) was added to the mixture, and the mixture was heated to 80° C. andstirred for 12 h. The mixture was filtered to remove solid impurities.The filtrate was concentrated in vacuo to remove the solvent, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=8/1) to give the title compound as a light yellow solid (230 mg,93%).

MS (ESI, pos. ion) m/z: 647.1 [M+H]⁺.

Step 3:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(230 mg, 0.35 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofsodium hydroxide (142 mg, 3.55 mmol) in water (2 mL). The mixture wasstirred at rt overnight. To the reaction mixture was added water (10mL), and the resulting mixture was acidified with hydrochloric acid (1M) to pH about 3 to 4. The mixture was extracted with ethyl acetate (20mL×3), and the combined organic layers were washed with saturated brine(50 mL), dried over anhydrous sodium sulfate, then filtered. Thefiltrate was concentrated in vacuo to remove the solvent and the residuewas purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1−5/1) to give the title compound as a white solid (120 mg,71%).

MS (ESI, pos. ion) m/z: 479.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 479.2024 [M+H]⁺, (C₂₆H₂₄F₂N₅O₂)[M+H]⁺theoretical value: 479.2007;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.21 (s, 1H), 8.58 (d, J=8.8 Hz,1H), 8.27 (s, 2H), 7.52 (s, 1H), 7.28 (d, J=4.1 Hz, 1H), 6.87 (s, 2H),4.69 (s, 1H), 3.74 (s, 3H), 2.87 (d, J=3.9 Hz, 1H), 2.00 (s, 2H), 1.80(m, 3H), 1.67-1.45 (m, 5H).

Example 65:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(347 mg, 0.50 mmol, 60%), (+/−)-trans-methyl3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(146 mg, 0.41 mmol), potassium carbonate (114 mg, 0.82 mmol),Pd(dppf)Cl₂ (30 mg, 0.04 mmol), 1,4-dioxane (5 mL) and water (0.5 mL).The air in the mixture was removed by bubbling with nitrogen for 10 min,then the mixture in the microwave tube was stirred at 110° C. withmicrowave heating for 2 hours. The mixture was filtered through a celitepad, and the filter cake was washed with ethyl acetate (50 mL). Thefiltrate was washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography(n-hexane/EtOAc (v/v)=5/1) to give the title compound as a yellow solid(214 mg, 56%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.75 (dd, J=9.0, 2.8 Hz, 1H), 8.67 (s,1H), 8.31 (d, J=1.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.27 (d, J=6.1 Hz,2H), 6.92 (d, J=3.4 Hz, 1H), 6.38 (d, J=3.3 Hz, 1H), 5.13 (d, J=6.9 Hz,1H), 4.90 (d, J=5.9 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.48 (d, J=5.6Hz, 1H), 2.37 (s, 3H), 2.07 (d, J=2.0 Hz, 2H), 2.01 (s, 1H), 1.94 (m,1H), 1.79 (m, 8H).

Step 2:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(197 mg, 0.33 mmol) in a mixed solvent of THF and MeOH (v/v=1/1, 6 mL)was added a aqueous sodium hydroxide solution (4 M, 0.90 mL, 3.60 mmol).The mixture was stirred at 30° C. overnight. To the reaction mixture wasadded water (10 mL), and the resulting mixture was acidified withhydrochloric acid (1 M) to pH about 5.5. The mixture was extracted withethyl acetate (20 mL×3), and the combined organic layers were washedwith saturated brine (50 mL), dried over anhydrous sodium sulfate, thenfiltered. The filtrate was concentrated in vacuo to remove the solventand the residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=10/1) to give the title compound as a yellow solid (80mg, 56%).

MS (ESI, pos. ion) m/z: 435.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 435.1941 [M+H]⁺, (C₂₃H₂₄FN₆O₂)[M+H]⁺theoretical value: 435.1945;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 12.09 (s, 1H), 8.73(d, J=8.5 Hz, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.22 (d, J=5.7 Hz, 1H),7.08 (s, 1H), 6.62 (s, 1H), 4.80 (s, 1H), 3.78 (s, 3H), 2.72 (d, J=5.7Hz, 1H), 2.03 (d, J=15.2 Hz, 2H), 1.80 (m, 3H), 1.49 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.22, 157.13, 156.03, 154.75,150.65, 146.43, 131.51, 131.22, 130.00, 124.76, 119.07, 118.99, 116.07,115.99, 115.95, 115.86, 101.15, 98.95, 50.63, 49.11, 31.05, 28.98,28.87, 26.09, 24.23, 21.59, 19.52.

Example 66:(+/−)-trans-3-((5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((5-chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (284 mg,1.55 mmol) and 5,7-dichlorothiazolo[5,4-d]pyrimidine (352 mg, 1.71 mmol)were dissolved in DMF (5 mL), then potassium carbonate (428 mg, 3.10mmol) was added. The mixture was stirred at rt overnight. The reactionwas stopped, and to the reaction mixture was added water (50 mL). Theresulting mixture was extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with saturated brine (80 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (PE/EtOAc (v/v)=10/1) to give thetitle compound as a yellow solid (317 mg, 58%).

MS (ESI, pos. ion) m/z: 353.0 [M+H]⁺;

¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.75 (s, 1H), 6.49 (d, J=4.7 Hz, 1H),4.63 (s, 1H), 3.76 (s, 3H), 2.50 (d, J=5.6 Hz, 1H), 2.01 (d, J=1.8 Hz,1H), 1.95 (d, J=2.5 Hz, 1H), 1.88-1.76 (m, 2H), 1.73-1.53 (m, 6H).

Step 2: (+/−)-trans-methyl3-((5-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(180 mg, 0.21 mmol, 50%), K₂CO₃ (39 mg, 0.28 mmol), PdCl₂(dppf) (8 mg,0.01 mmol) and (+/−)-trans-methyl3-((5-chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(51 mg, 0.14 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 2 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1-5/1) to give thetitle compound as a white solid (61 mg, 70%).

Step 3:(+/−)-trans-3-((5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a mixed solvent of THF and MeOH (v/v=2 mL/2 mL) was added(+/−)-trans-methyl3-((5-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(61 mg, 0.10 mmol), then a solution of NaOH (40 mg, 1.00 mmol) in water(1 mL) was added. The resulting mixture was stirred overnight at rt,then water (10 mL) was added. The mixture was acidified withhydrochloric acid (1 M) to pH about 6, then extracted with ethyl acetate(15 mL×3). The combined organic layers were washed with saturated brine(40 mL), dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo, and the residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=10/1-5/1) to give the titlecompound as a white solid (16 mg, 36%).

MS (ESI, pos. ion) m/z: 439.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 439.1329, (C₂₁H₂₀FN₆O₂S)[M+H]⁺ theoreticalvalue: 439.1352;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.38 (s, 1H), 9.13 (s, 1H), 8.63 (d,J=9.4 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.21 (d, J=6.5 Hz, 1H), 4.89(s, 1H), 3.03 (d, J=5.4 Hz, 1H), 2.03 (s, 2H), 1.83 (m, 3H), 1.70-1.43(m, 5H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 162.39, 159.26, 155.57, 155.35,150.28, 146.39, 132.01, 131.87, 131.82, 128.61, 118.97, 118.92, 115.79,115.65, 114.35, 114.32, 51.02, 47.92, 28.90, 28.77, 25.62, 24.34, 21.64,19.59.

Example 67:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((2-chloro-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

(+/−)-trans-Methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (400 mg,2.18 mmol) and 2,6-dichloro-9-methyl-9H-purine (400 mg, 1.97 mmol) weredissolved in acetonitrile (8 mL), then DIPEA (1.75 mL, 9.95 mmol) wasadded. The mixture was stirred at 50° C. overnight under nitrogenprotection. To the reaction mixture was added water (50 mL), and theresulting mixture was partitioned. The aqueous layer was extracted withethyl acetate (50 mL×2). The combined organic layers were washed withsaturated brine (80 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to remove the solventand the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=3/1) to give the title compound as a yellow solid (457mg, 66%).

MS (ESI, pos. ion) m/z: 350.1 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.66 (s, 1H), 6.37 (s, 1H), 4.55 (s,1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.21 (s, 1H), 2.43 (s, 1H), 1.94 (s,1H), 1.88 (d, J=2.5 Hz, 1H), 1.78 (d, J=10.6 Hz, 2H), 1.66-1.44 (m, 5H).

Step 2: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (8 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(540 mg, 0.52 mmol, 40%), K₂CO₃ (119 mg, 0.86 mmol), PdCl₂(dppf) (29 mg,0.04 mmol) and (+/−)-trans-methyl3-((2-chloro-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(151 mg, 0.43 mmol). Then H₂O (1 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 2 h at 110° C. with microwave heating. Themixture was filtered through a celite pad to remove solid impurities.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1-2/1) to give thetitle compound as a white solid (166 mg, 64%).

Step 3:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-9-methyl-9H-purin-6-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(166 mg, 0.28 mmol) in THF/MeOH (v/v=3 mL/3 mL) was added a solution ofNaOH (112 mg, 2.8 mmol) in water (2 mL). The mixture was stirred at rtovernight, then acidified with hydrochloric acid (1 M) to pH about 6.The resulting mixture was extracted with ethyl acetate (15 mL×3). Thecombined organic layers were washed with saturated brine (40 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent and the residue was purifiedby silica gel column chromatography (DCM/MeOH (v/v)=10/1-5/1) to givethe title compound as a white solid (71 mg, 59%).

MS (ESI, pos. ion) m/z: 436.1 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 436.1874, (C₂₂H₂₃FN₇O₂)[M+H]⁺ theoreticalvalue: 436.1897;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.26 (s, 2H), 8.70 (s, 1H), 8.25 (d,J=10.4 Hz, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 4.83 (s, 1H), 3.79 (s, 3H),2.95 (s, 1H), 2.00 (s, 2H), 1.84-1.74 (m, 3H), 1.50 (m, 5H);

¹³C NMR (101 MHz, DMSO-d₆) δ (ppm): 176.19, 157.22, 157.08, 154.84,146.36, 141.10, 131.67, 131.38, 130.58, 119.01, 118.93, 115.33, 110.00,61.82, 50.56, 48.35, 29.69, 28.89, 25.80, 24.28, 21.63, 19.50.

Example 68:(+/−)-trans-3-((6-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (+/−)-trans-methyl3-((2-chloro-6-cyclopropylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2,6-dichloropyrimidin-4-yl)amino) bicyclo[2.2.2]octane-2-carboxylate (100 mg, 0.30 mmol) in tetrahydrofuran (5 mL) wereadded Pd(dppf)Cl₂ (25 mg, 0.03 mmol), potassium phosphate (160 mg, 0.75mmol) and cyclopropylboronic acid (27 mg, 0.31 mmol). The mixture wasrefluxed overnight under nitrogen protection. The reaction mixture wascooled to rt and concentrated in vacuo to dry. To the residue was addedethyl acetate (20 mL), and the mixture was washed with saturated aqueoussodium bicarbonate (20 mL) and saturated brine (20 mL). The organiclayer was dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated in vacuo to dry and the residue was purifiedby silica gel column chromatography (PE/EA (v/v)=5/1) to give the titlecompound as colorless oil (59 mg, 58%).

MS (ESI, pos. ion) m/z: 336.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.18 (s, 1H), 5.37-5.13 (m, 1H), 4.17(d, J=19.1 Hz, 1H), 3.76-3.73 (m, 3H), 2.35-2.31 (m, 1H), 2.07-2.03 (m,1H), 1.84-1.79 (m, 2H), 1.70 (d, J=7.3 Hz, 2H), 1.65 (d, J=7.0 Hz, 2H),1.54 (d, J=10.7 Hz, 2H), 1.46 (d, J=7.3 Hz, 1H), 1.36-1.23 (m, 1H), 1.08(tt, J=9.1, 4.5 Hz, 2H), 1.02-0.96 (m, 2H).

Step 2: (+/−)-trans-methyl3-((6-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1.03 g, 1.49 mmol, 60%), (+/−)-trans-methyl3-((2-chloro-6-cyclopropylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(400 mg, 1.191 mmol), water (0.5 mL), 1,4-dioxane (15 mL), potassiumcarbonate (442 mg, 3.20 mmol) and Pd(dppf)Cl₂ (130 mg, 0.16 mmol). Theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 1 h at 110° C. with microwave heating. Themixture was filtered through a celite pad, and the filter cake waswashed with ethyl acetate (50 mL). The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(PE/EA (v/v)=15/1) to give the title compound as light yellow oil (251mg, 36%).

MS (ESI, pos. ion) m/z: 590.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.57 (s, 1H), 8.49 (dd, J=9.0, 2.7 Hz,1H), 8.32 (s, 1H), 8.30 (s, 1H), 8.10 (d, J=6.1 Hz, 2H), 8.09 (s, 2H),6.20 (s, 1H), 5.03 (s, 1H), 3.77 (s, 1H), 3.74 (s, 3H), 2.38 (s, 3H),1.95-1.87 (m, 4H), 1.79 (s, 4H), 1.01 (dt, J=11.3, 5.5 Hz, 4H).

Step 3:(+/−)-trans-3-((6-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((6-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(250 mg, 0.42 mmol) in a mixed solvent of THF (5 mL), methanol (5 mL)and water (5 mL), then to the mixture was added NaOH (170 mg, 4.25 mmol)in portions. The mixture was stirred at rt overnight and concentrated invacuo to remove the organic solvent. To the residue was added water (15mL), and the resulting mixture was acidified with diluted hydrochloricacid (1 mol/L) to pH about 6. The resulting mixture was extracted withethyl acetate (20 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to remove the solventand the residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=30/1-10/1) to give the title compound as a white solid(90 mg, 50%).

MS (ESI, pos. ion) m/z: 422.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 422.1964 [M+H]⁺, (C₂₃H₂₆FN₅O₂)[M+H]⁺theoretical value: 422.1992;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.96 (s, 1H), 8.79 (s, 1H), 8.40 (s,1H), 7.26 (s, 1H), 7.18 (s, 1H), 7.09 (s, 1H), 6.07 (s, 1H), 4.78 (s,1H), 2.55 (s, 1H), 2.12 (s, 1H), 2.04 (s, 1H), 1.91 (s, 1H), 1.73-1.39(m, 8H), 1.12 (d, J=4.3 Hz, 2H), 1.00 (s, 2H);

¹³C NMR (151 MHz, DMSO-d₆) δ (ppm): 175.37, 162.36, 159.01, 158.81,157.35, 155.74, 146.17, 134.80, 133.52, 133.33, 118.79, 118.74, 115.81,115.67, 95.75, 51.41, 48.79, 29.07, 28.45, 25.60, 24.09, 21.50, 21.20,19.33, 12.87, 10.50, 10.34.

Example 69:(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

Step 1: (R)-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To a reaction flask were added 2,4,6-trichloro-5-fluoropyrimidine (0.64g, 3.16 mmol), DIPEA (1.02 g, 7.91 mmol), (R)-methyl3-amino-4,4-dimethylpentanoate (0.42 g, 2.63 mmol) and dichloromethane(10 mL), and the reaction mixture was stirred at rt for 24 h. To thereaction mixture was added water (20 mL), and the resulting mixture wasextracted with dichloromethane (20 mL×3). The combined organic layerswere washed with saturated brine (30 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a light yellow solid (420 mg,49%).

MS (ESI, pos. ion) m/z: 324.10[M+H]⁺.

Step 2: (R)-methyl3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To acetonitrile (25 mL) were added (R)-methyl3-((2,6-dichloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate(420 mg, 1.29 mmol), phenylboronic acid (680 mg, 2.09 mmol), potassiumacetate (617 mg, 6.29 mmol) and Pd(dppf)Cl₂ (171 mg, 0.21 mmol), then tothe mixture was added water (1 mL). The resulting mixture was stirred at80° C. for 12 h under nitrogen protection. The mixture was filtered toremove solid impurities. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a yellow solid (480 mg, 63%).

MS (ESI, pos. ion) m/z: 366.2[M+H]⁺.

Step 3: (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(695 mg, 0.75 mmol, 45%), potassium carbonate (337 mg, 2.73 mmol),palladium acetate (30 mg, 0.14 mmol), X-Phos (130 mg, 0.27 mmol) and(R)-methyl3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate(250 mg, 0.68 mmol). Then H₂O (1 mL) was added to the mixture, and themixture was heated to 100° C. under nitrogen protection and stirred for12 h. The mixture was filtered to remove solid impurities. The filtratewas concentrated in vacuo, and the residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=8/1) to give the title compound asa light yellow solid (200 mg, 47%).

MS (ESI, pos. ion) m/z: 620.2 [M+H]⁺.

Step 4:(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid

To a solution of (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate(200 mg, 0.33 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (129 mg, 3.22 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1−5/1) to give the title compound as awhite solid (40 mg, 27%).

MS (ESI, pos. ion) m/z: 452.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 452.1896 [M+H]⁺, (C₂₄H₂₄F₂N₅O₂)[M+H]⁺theoretical value: 452.1898;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.38 (s, 1H), 8.62 (d, J=9.0 Hz,1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.04 (d, J=6.6 Hz, 2H), 7.68 (s, 1H),7.59 (d, J=7.5 Hz, 3H), 4.89 (s, 1H), 2.76-2.58 (m, 2H), 1.22 (s, 1H),1.00 (s, 9H).

Example 70:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

Step 1: (R)-methyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate

A suspension of 2,4-dichloro-6-(furan-2-yl)pyrimidine (0.30 g, 1.40mmol), potassium carbonate (0.39 g, 2.80 mmol), (R)-methyl3-amino-4,4-dimethylpentanoate (0.48 g, 1.80 mmol) in DMF (10 mL) wasstirred at 80° C. for 24 h. To the reaction mixture was added water (40mL), and the resulting mixture was extracted with ethyl acetate (30mL×3). The combined organic layers were washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=15/1) to give the title compound as apale solid (300 mg, 64%).

MS (ESI, pos. ion) m/z: 338.2[M+H]⁺.

Step 2: (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(821 mg, 0.88 mmol, 45%), potassium carbonate (491 mg, 3.55 mmol),palladium acetate (39 mg, 0.17 mmol), X-Phos (169 mg, 0.35 mmol) and(R)-methyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(300 mg, 0.88 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 100° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(300 mg, 57%).

MS (ESI, pos. ion) m/z: 592.2 [M+H]⁺.

Step 3:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

To a solution of (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(300 mg, 0.50 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (202 mg, 5.07 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to removethe solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (180 mg, 83%).

MS (ESI, pos. ion) m/z: 424.3[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 424.1793[M+H]⁺, (C₂₂H₂₃FN₅O₃)[M+H]⁺theoretical value: 424.1785;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.25 (s, 1H), 12.05 (s, 1H), 8.67(d, J=9.0 Hz, 1H), 8.30 (d, J=10.6 Hz, 2H), 7.88 (s, 1H), 7.34 (d, J=9.4Hz, 1H), 7.23 (s, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 4.82 (s, 1H), 2.68(d, J=12.7 Hz, 1H), 2.35-2.23 (m, 1H), 0.98 (s, 9H).

Example 71:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid

Step 1: (R)-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To the reaction flask were added 2,4-dichloro-6-phenylpyrimidine (0.30g, 1.30 mmol), potassium carbonate (0.37 g, 2.70 mmol), (R)-methyl3-amino-4,4-dimethylpentanoate (0.46 g, 1.70 mmol) and DMF (10 mL). Themixture was stirred at 80° C. for 24 h. Water (40 mL) was added, and theresulting mixture was extracted with EtOAc (30 mL×3). The combinedorganic phases were washed with saturated brine (60 mL), dried overanhydrous Na₂SO₄, filtered, and the filtrate was concentrated in vacuo.The residue was purified by silica gel chromatograph (PE/EtOAc(v/v)=15/1) to give the title compound as a white solid (120 mg, 26%).

MS (ESI, pos. ion) m/z: 348.1[M+H]⁺.

Step 2: (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(383 mg, 0.41 mmol, 45%), potassium carbonate (190 mg, 1.38 mmol),palladium acetate (15 mg, 0.07 mmol), X-Phos (65 mg, 0.14 mmol) and(R)-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate (120mg, 0.34 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 100° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(180 mg, 86%).

MS (ESI, pos. ion) m/z: 602.3 [M+H]⁺.

Step 3:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

To a solution of (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)-4,4-dimethylpentanoate(180 mg, 0.30 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (120 mg, 2.99 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to removethe solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (94 mg, 72%).

MS (ESI, pos. ion) m/z: 434.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 434.2013[M+H]⁺, (C₂₄H₂₅FN₅O₂)[M+H]⁺theoretical value: 434.1992;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.26 (s, 1H), 12.05 (s, 1H), 8.70(d, J=9.3 Hz, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 8.09 (d, J=6.6 Hz, 2H),7.54 (dt, J=13.2, 6.8 Hz, 3H), 7.30 (d, J=9.0 Hz, 1H), 6.82 (s, 1H),4.86 (s, 1H), 2.70 (d, J=12.8 Hz, 1H), 2.38-2.24 (m, 1H), 0.99 (s, 9H).

Example 72:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

Step 1: (R)-methyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To a reaction flask were added2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 1.30mmol), potassium carbonate (0.36 g, 2.61 mmol), (R)-methyl3-amino-4,4-dimethylpentanoate (0.42 g, 1.56 mmol) and DMF (10 mL), andthe mixture was stirred at 80° C. for 24 h. After the reaction wascompleted, to the reaction mixture was added water (20 mL), and theresulting mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layers were washed with saturated brine (60 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=15/1) to give the title compound as apale solid (260 mg, 56%).

MS (ESI, pos. ion) m/z: 353.10[M+H]⁺.

Step 2: (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoate

To THF (10 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(749 mg, 0.81 mmol, 45%), potassium carbonate (407 mg, 2.95 mmol),palladium acetate (33 mg, 0.15 mmol), X-Phos (140 mg, 0.30 mmol) and(R)-methyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoate (260 mg, 0.74 mmol). Then H₂O (0.5 mL) was added to themixture, and the mixture was heated to 100° C. and stirred for 12 h. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=8/1) to give the title compound as alight yellow solid (310 mg, 69%).

MS (ESI, pos. ion) m/z: 607.3 [M+H]⁺.

Step 3:(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid

To a solution of (R)-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(300 mg, 0.49 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (197 mg, 4.95 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (180 mg, 83%).

MS (ESI, pos. ion) m/z: 439.3[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 439.2271[M+H]⁺, (C₂₃H₂FN₆O₂)[M+H]⁺ theoreticalvalue: 439.2258;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.06 (s, 1H), 11.94 (s, 1H), 8.74(d, J=9.4 Hz, 1H), 8.23 (d, J=18.8 Hz, 2H), 7.18 (d, J=3.0 Hz, 1H), 7.04(d, J=8.9 Hz, 1H), 6.70 (d, J=3.0 Hz, 1H), 5.09-4.96 (m, 2H), 2.70 (d,J=12.7 Hz, 1H), 1.50 (dd, J=6.2, 3.5 Hz, 6H), 1.24 (s, 2H), 1.00 (s,9H).

Example 73:(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a reaction flask were added 2,4-dichloro-6-(furan-2-yl)pyrimidine(0.50 g, 2.30 mmol), potassium carbonate (0.83 g, 6.00 mmol),(2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride(0.70 g, 3.00 mmol) and DMF (10 mL). The mixture was stirred at 50° C.for 24 h. To the reaction mixture was added water (40 mL), and theresulting mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layers were washed with saturated brine (60 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=15/1) to give the title compound as apale solid (610 mg, 70%).

MS (ESI, pos. ion) m/z: 376.0[M+H]⁺.

Step 3: 3-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine

To a solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (2.50 g, 18.36 mmol)in DMF (50 mL) was added a solution of bromine (3.20 g, 20.00 mmol) inDMF (20 mL) at 0° C. After the addition, the mixture was stirred at rtfor 2 h. To the mixture was added water (100 mL), then there was a lotof solid precipitated out. The mixture was filtered under reducedpressure, and the filter cake was washed with water (30 mL) for twotimes and then dried in vacuo at 60° C. for 24 h to give the titlecompound as a white solid (3.44 g, 87%).

MS (ESI, pos. ion) m/z: 217.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.20 (s, 1H), 8.04-7.95 (m, 1H),7.67 (d, J=2.5 Hz, 1H), 6.94 (t, J=9.7 Hz, 1H).

Step 4: 3-bromo-6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a solution of 3-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (3.44 g,16.00 mmol) in THF (68 mL) was added sodium hydride (1.30 g, 32.00 mmol,60%) at 0° C. Then the reaction mixture was stirred for 30 min at 0° C.TsCl (4.58 g, 24.00 mmol) was added and the reaction mixture was stirredat rt for 3 h. Water (200 mL) was added to quench the reaction, and theresulting mixture was extracted with EtOAc (100 mL×2). The combinedorganic phases were washed with saturated brine (200 mL), dried overanhydrous Na₂SO₄, filtered, and the filtrate was concentrated in vacuo.The residue was purified by silica gel chromatograph to give the titlecompound as a brown solid (5.70 g, 97%).

MS (ESI, pos. ion) m/z: 369.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.11 (d, J=8.2 Hz, 2H), 7.88 (t, J=7.8Hz, 1H), 7.75 (s, 1H), 7.34 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.3 Hz, 1H),2.41 (s, 3H).

Step 5:6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a suspension of 3-bromo-6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(5.70 g, 15.00 mmol), tetrakis(triphenylphosphine)platinum (1.80 g, 1.50mmol) and potassium acetate (4.50 g, 46.00 mmol) in 1,4-dioxane (120 mL)was added bis(pinacolato)diboron (5.90 g, 23.00 mmol). The mixture wasstirred at 100° C. for 24 h under nitrogen protection. To the reactionmixture was added ethyl acetate (50 mL), and the mixture was filteredthrough a celite pad. The filter cake was washed with ethyl acetate (20mL×2). The combined filtrates was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=40/1)to give the title compound as a yellow solid (3.50 g, 54%).

MS (ESI, pos. ion) m/z: 417.30 [M+H]⁺.

Step 6: (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(610 mg, 0.64 mmol, 45%), potassium carbonate (338 mg, 2.45 mmol),palladium acetate (27 mg, 0.12 mmol), X-Phos (116 mg, 0.24 mmol) and(2S,3S)-ethyl3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(230 mg, 0.61 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(260 mg, 67%).

MS (ESI, pos. ion) m/z: 630.1 [M+H]⁺.

Step 7:(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(260 mg, 0.41 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (146 mg, 4.12 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (150 mg, 81%).

MS (ESI, pos. ion) m/z: 448.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 448.1793[M+H]⁺, (C₂₄H₂₃FN₅O₃)[M+H]⁺theoretical value: 448.1785;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.21 (s, 1H), 9.00 (s, 1H), 8.20 (s,1H), 7.88 (s, 1H), 7.55 (s, 1H), 7.28 (s, 1H), 6.98 (d, J=8.4 Hz, 1H),6.70 (s, 1H), 6.66 (s, 1H), 4.59 (s, 1H), 2.51 (s, 1H), 1.94 (s, 1H),1.80-1.71 (m, 2H), 1.68 (s, 1H), 1.62-1.53 (m, 3H), 1.48-1.36 (m, 3H).

Example 74:(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To the reaction flask were added2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (0.60 g, 2.61mmol), potassium carbonate (1.01 g, 7.31 mmol), (2S,3S)-ethyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (0.85 g, 3.65mmol) and DMF (10 mL), and the mixture was stirred at 50° C. for 24 h.Water (20 mL) was added to quench the reaction, and the resultingmixture was extracted with EtOAc (30 mL×3). The combined organic phaseswere washed with saturated brine (60 mL), dried over anhydrous Na₂SO₄,filtered, and the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatograph (PE/EtOAc (v/v)=15/1) to give thetitle compound as a pale solid (732 mg, 71%).

MS (ESI, pos. ion) m/z: 391.10[M+H]⁺.

Step 3: (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(580 mg, 0.56 mmol, 40%), potassium carbonate (282 mg, 2.05 mmol),palladium acetate (22 mg, 0.10 mmol), X-Phos (97 mg, 0.20 mmol) and(2S,3S)-ethyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.51 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(280 mg, 84%).

MS (ESI, pos. ion) m/z: 645.3 [M+H]⁺.

Step 4:(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(280 mg, 0.43 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (173 mg, 4.34 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (180 mg, 89%).

MS (ESI, pos. ion) m/z: 463.2[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 463.2268[M+H]⁺, (C₂₅H₂₈FN₆O₂)[M+H]⁺theoretical value: 463.2258;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.04 (s, 1H), 9.04 (t, J=8.1 Hz,1H), 8.05 (s, 1H), 7.22 (d, J=6.3 Hz, 1H), 7.19 (s, 1H), 6.94 (d, J=8.6Hz, 1H), 6.66 (s, 1H), 5.01 (d, J=6.6 Hz, 1H), 4.75 (s, 1H), 2.68 (s,1H), 1.98 (s, 1H), 1.75 (m, 3H), 1.51 (m, 11H).

Example 75(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a reaction flask were added 2,4-dichloro-6-phenylpyrimidine (0.76 g,3.40 mmol), potassium carbonate (0.93 g, 6.80 mmol), (2S,3S)-ethyl3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride (0.96 g, 4.10mmol) and DMF (10 mL). The mixture was stirred at 50° C. for 24 h. Water(40 mL) was added to quench the reaction, and the resulting mixture wasextracted with EtOAc (30 mL×3). The combined organic phases were washedwith saturated brine (60 mL), dried over anhydrous Na₂SO₄, filtered, andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatograph (PE/EtOAc (v/v)=15/1) to give the titlecompound as a white solid (0.70 g, 50%).

MS (ESI, pos. ion) m/z: 386.1[M+H]⁺.

Step 3: (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(503 mg, 0.54 mmol, 45%), potassium carbonate (286 mg, 2.07 mmol),palladium acetate (23 mg, 0.10 mmol), X-Phos (98 mg, 0.20 mmol) and(2S,3S)-ethyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.52 mmol). Then H₂O (0.5 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove solid impurities. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a pale yellow solid(240 mg, 72%).

MS (ESI, pos. ion) m/z: 640.2 [M+H]⁺.

Step 4:(2S,3S)-3-((2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (2S,3S)-ethyl3-((2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(240 mg, 0.37 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (150 mg, 3.75 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (150 mg, 87%).

MS (ESI, pos. ion) m/z: 458.1[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 458.2003[M+H]⁺, (C₂₆H₂₅FN₅O₂)[M+H]⁺theoretical value: 458.1992;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.36-12.25 (m, 1H), 12.21 (s, 1H),9.03 (s, 1H), 8.23 (s, 1H), 8.12 (s, 2H), 7.61-7.48 (m, 4H), 7.00 (d,J=8.3 Hz, 1H), 6.79 (s, 1H), 4.62 (s, 1H), 1.99 (s, 3H), 1.69 (m, 8H).

Example 76:(+/−)-trans-3-((5-fluoro-2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (+/−)-trans-methyl3-((5-fluoro-2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To THF (10 mL) were added6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(517 mg, 0.49 mmol, 40%), potassium carbonate (262 mg, 1.89 mmol),palladium acetate (21 mg, 0.09 mmol), X-Phos (90 mg, 0.18 mmol) and(+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(180 mg, 0.47 mmol). Then H₂O (1 mL) was added to the mixture, and themixture was heated to 80° C. and stirred for 12 h. The mixture wasfiltered to remove the solid impurity. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=8/1) to give the title compound as a light yellow solid(240 mg, 79%).

MS (ESI, pos. ion) m/z: 634.1 [M+H]⁺.

Step 2:(+/−)-trans-3-((5-fluoro-2-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(6-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(240 mg, 0.38 mmol) in THF/MeOH (v/v=8 mL/4 mL) was added a solution ofNaOH (150 mg, 3.75 mmol) in water (2 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 3 to 4. The resultingmixture was extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as awhite solid (150 mg, 85%).

MS (ESI, pos. ion) m/z: 466.3[M+H]⁺;

HRMS (ESI, pos. ion) m/z: 466.1702 [M+H]⁺, (C₂₄H₂₂F₂N₅O₃)[M+H]⁺theoretical value: 466.1691;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.29 (s, 1H), 12.20 (s, 1H), 8.96(t, J=8.4 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.61 (d, J=6.8Hz, 1H), 7.27 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 4.67 (s,1H), 2.86 (d, J=6.8 Hz, 1H), 2.01 (s, 1H), 1.97 (s, 1H), 1.78 (s, 3H),1.65-1.39 (m, 5H).

Example 77:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: 1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone

To a mixture of glacial acetic acid (40 mL) and sulfuric acid solution(64 mL, 1.5 mol/L) was added 2,4-dichloro-5-fluoropyrimidine (2.00 g,12.00 mmol). To the mixture was added acetaldehyde aqueous solution (16mL, 100 mmol, 40% wt), then ammonium sulfate solution (24 mL, 24 mmol, 1mol/L) and ferrous sulfate (24 mL, 36 mmol, 1.5 mol/L) were addeddropwise successively. The resulting mixture was stirred at 10° C. for 2h. The mixture was filtered to give the title compound as a gray whitesolid (436 mg, 17%).

MS (ESI, pos. ion) m/z: 210.9 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.72 (s, 3H).

Step 2: (+/−)-trans-methyl3-((6-acetyl-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (53 mg, 0.29 mmol) and1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone (50 mg, 0.24 mmol) inTHF (5 mL) was added DIPEA (0.2 mL, 0.96 mmol), and the mixture wasstirred at rt overnight. The mixture was diluted with water (40 mL), andthe resulting mixture was extracted with ethyl acetate (40 mL×3). Thecombined organic layers were washed with saturated brine (50 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dry. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=5/1) to give the title compound asa white solid (33 mg, 39%).

MS (ESI, pos. ion) m/z: 356.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.56 (s, 1H), 4.51 (s, 1H), 3.78 (s,3H), 2.62 (s, 3H), 2.40 (d, J=5.8 Hz, 1H), 2.03 (s, 1H), 1.90 (s, 1H),1.67 (d, J=11.0 Hz, 8H).

Step 3: (+/−)-trans-methyl3-((2-chloro-6-((E)-3-(dimethylamino)acryloyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

A solution of (+/−)-trans-methyl3-((6-acetyl-2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (33 mg, 0.09 mmol) in DMF-DMA(1 mL) was stirred at rt overnight. To the reaction mixture was addedwater (25 mL), and the resulting mixture was extracted with ethylacetate (25 mL×3). The combined organic layers were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) togive the title compound as yellow oil (33 mg, 87%).

MS (ESI, pos. ion) m/z: 411.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.84 (s, 1H), 5.87 (s, 1H), 5.46 (s,1H), 4.49 (s, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 2.97 (s, 3H), 2.40 (d,J=5.8 Hz, 1H), 2.01 (s, 1H), 1.89 (s, 1H), 1.67 (s, 8H).

Step 4: (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-((2-chloro-6-((E)-3-(dimethylamino)acryloyl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(200 mg, 0.4867 mmol) in ethanol (3 mL) was added hydroxylammoniumchloride (67 mg, 0.96 mmol). The reaction mixture was stirred at 78° C.overnight. The mixture was concentrated in vacuo to remove the solventand the residue was dissolved in ethyl acetate (20 mL). The mixture waswashed with saturated brine (20 mL), dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) togive the title compound as a red solid (35 mg, 19%).

MS (ESI, pos. ion) m/z: 381.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.40 (d, J=1.6 Hz, 1H), 6.99 (s, 1H),5.63 (d, J=3.8 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 3.78 (s, 3H), 2.45 (d,J=5.8 Hz, 1H), 2.04 (d, J=2.2 Hz, 1H), 1.93 (d, J=2.2 Hz, 1H), 1.77-1.60(m, 8H).

Step 5: (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tube were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(170 mg, 0.25 mmol), (+/−)-trans-methyl3-((2-chloro-5-fluoro-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (78 mg, 0.21 mmol), water (0.2 mL), 1,4-dioxane (3mL), potassium carbonate (84 mg, 0.61 mmol) and X-phos (19 mg, 0.04mmol). The air in the mixture was removed by bubbling with nitrogen for10 min. The mixture was stirred for 3 h at 110° C. with microwaveheating. The filtrate was concentrated in vacuo to dry and the residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) togive the title compound as yellow oil (28 mg, 22%).

MS (ESI, pos. ion) m/z: 637.2 [M+H]⁺.

Step 6:(+/−)-trans-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(isoxazol-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(27 mg, 0.04 mmol) in THF/MeOH (v/v=1/1, 2 mL) was added aqueous sodiumhydroxide solution (4 M, 0.10 mL, 0.40 mmol). The mixture was stirred at30° C. overnight, then diluted with water (10 mL). The resulting mixturewas acidified with hydrochloric acid (1 M) to pH about 5.5, thenextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a yellow solid (15 mg, 76%).

MS (ESI, pos. ion) m/z: 467.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 467.1644 [M+H]⁺, (C₂₃H₂₁F₂N₆O₃)[M+H]⁺theoretical value: 467.1643;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.39 (s, 1H), 9.19 (s, 1H), 8.53 (d,J=9.5 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.88 (d, J=6.2 Hz, 1H), 7.24(s, 1H), 4.75 (s, 1H), 2.89 (s, 1H), 2.03 (s, 1H), 1.87-1.73 (m, 3H),1.70-1.42 (m, 6H).

Example 78:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

Step 1: (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride

The title compound can be prepared according to the synthetic methoddisclosed in patent application WO 2015073491.

Step 2: (2S,3S)-ethyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a solution of (2S,3S)-ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylatehydrochloride (458 mg, 1.96 mmol),2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (410 mg, 1.78 mmol)in dichloromethane (15 mL) was added slowly DIPEA (0.97 mL, 5.88 mmol).The mixture was stirred at 30° C. overnight under nitrogen protection.The reaction mixture was washed with water (10 mL), 5% aqueous sodiumbisulfate solution (10 mL) and saturated brine (10 mL) in turn, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as ayellow solid (333 mg, 50%).

Step 3: (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To 1,4-dioxane (3 mL) were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(284 mg, 0.31 mmol, 45% wt), potassium carbonate (106 mg, 0.77 mmol),PdCl₂(dppf) (41 mg, 0.05 mmol) and (2S,3S)-ethyl3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(100 mg, 0.26 mmol). Then H₂O (0.2 mL) was added to the mixture, and theair in the mixture was removed by bubbling with nitrogen for 10 min. Themixture was stirred for 2 h at 110° C. with microwave heating. Themixture was filtered to remove solid impurities. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1-5/1) to give the title compound as awhite solid (146 mg, 89%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.73 (dd, J=9.1, 2.7 Hz, 1H), 8.66 (s,1H), 8.32 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.30 (s, 2H), 7.06 (d, J=3.5Hz, 1H), 6.41 (d, J=2.9 Hz, 1H), 4.90 (s, 1H), 2.45 (d, J=5.2 Hz, 1H),2.38 (s, 3H), 2.08 (s, 2H), 2.00-1.66 (m, 8H), 1.57 (d, J=6.7 Hz, 6H),1.28 (s, 5H).

Step 4:(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (2S,3S)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(146 mg, 0.23 mmol) in THF/MeOH (v/v=5 mL/5 mL) was added a solution ofNaOH (90 mg, 2.26 mmol) in water (1 mL). The mixture was stirred at rtovernight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH about 6. The resultingmixture was extracted with ethyl acetate (15 mL×3). The combined organiclayers were washed with saturated brine (40 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo toremove the solvent and the residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1-5/1) to give the title compound as ayellow solid (65 mg, 62%).

MS (ESI, pos. ion) m/z: 463.4 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 463.2264 [M+H]⁺, (C₂₈H₂₈FN₆O₂)[M+H]⁺theoretical value: 463.2258;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.28 (s, 1H), 12.08 (s, 1H), 8.68(d, J=8.8 Hz, 1H), 8.26 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.5Hz, 2H), 6.64 (s, 1H), 5.02 (m, 1H), 4.79 (s, 1H), 2.72 (d, J=6.3 Hz,1H), 2.03 (d, J=12.3 Hz, 2H), 1.79 (m, 3H), 1.54 (m, 11H).

Example 79:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 4-(4-(2,6-dichloropyrimidin-4-yl)phenyl)morpholine

To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) intetrahydrofuran (8.18 mL) were added palladium acetate (63 mg, 0.28mmol), triphenylphosphine (150 mg, 0.548 mmol),(4-morpholinophenyl)boronic acid (570 mg, 2.75 mmol) and aqueous sodiumcarbonate solution (1 M, 8.18 mL, 8.18 mmol). The mixture was stirred at70° C. for 6 h under nitrogen protection, then water (50 mL) was added.The mixture was extracted with EtOAc (50 mL×3). The combined organiclayers were washed with saturated brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo andthe residue was purified by silica gel column chromatography (PE) togive the title compound as a white solid (374 mg, 44%).

MS (ESI, pos. ion) m/z: 310.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.04 (d, J=9.1 Hz, 2H), 7.56 (s, 1H),6.96 (d, J=9.1 Hz, 2H), 3.92-3.88 (m, 4H), 3.37-3.33 (m, 4H).

Step 2: (+/−)-trans-methyl3-((2-chloro-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicycle[2.2.2]octane-2-carboxylate

To a solution of (+/−)-trans-methyl3-aminobicyclo[2.2.2]octane-2-carboxylate (230 mg, 1.25 mmol) and4-(4-(2,6-dichloropyrimidin-4-yl)phenyl)morpholine (353 mg, 1.14 mmol)in DMF (5 mL) was added potassium carbonate (173 mg, 1.25 mmol), and themixture was stirred at rt overnight. To the reaction mixture was addedwater (40 mL), and the resulting mixture was extracted with ethylacetate (40 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dry and the residuewas purified by silica gel column chromatography (PE/EA (v/v)=20/1) togive the title compound as a white solid (192 mg, 37%).

MS (ESI, pos. ion) m/z: 457.3 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.96 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9Hz, 2H), 6.71 (s, 1H), 5.41-5.34 (m, 1H), 4.32 (s, 1H), 3.92-3.86 (m,4H), 3.75 (s, 3H), 3.32-3.25 (m, 4H), 2.39 (d, J=4.8 Hz, 1H), 2.07 (d,J=3.3 Hz, 1H), 1.88 (d, J=2.7 Hz, 1H), 1.81-1.62 (m, 6H), 1.53-1.41 (m,2H).

Step 3: (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a sealed tub were added5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(396 mg, 0.38 mmol), (+/−)-trans-methyl3-((2-chloro-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(145 mg, 0.32 mmol), potassium carbonate (131 mg, 0.95 mmol),Pd(dppf)Cl₂ (51 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL).The air in the mixture was removed by bubbling with nitrogen for 10 minand the mixture in sealed tub was stirred at 110° C. for 2 h. Thereaction mixture was filtered through a celite pad, and the filter cakewas washed with ethyl acetate (50 mL). The filtrate was washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (n-hexane/EtOAc (v/v)=5/1)to give the title compound as a yellow solid (148 mg, 66%).

MS (ESI, pos. ion) m/z: 712.2[M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.71 (dd, J=8.1, 3.6 Hz, 2H), 8.33 (d,J=1.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 2H), 8.07 (d, J=8.8 Hz, 2H), 7.30 (s,2H), 7.04 (d, J=8.9 Hz, 2H), 6.67 (s, 1H), 5.12 (s, 1H), 4.52 (s, 1H),3.96-3.87 (m, 4H), 3.35-3.26 (m, 4H), 2.45 (d, J=4.9 Hz, 1H), 2.39 (s,3H), 2.10 (s, 1H), 1.98 (s, 1H), 1.84 (d, J=10.1 Hz, 2H), 1.69 (m, 6H).

Step 4:(+/−)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(4-morpholinophenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(144 mg, 0.20 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added aqueous sodiumhydroxide solution (4 M, 0.5 mL, 2 mmol). The mixture was stirred at 30°C. overnight, then diluted with water (10 mL). The resulting mixture wasacidified with hydrochloric acid (1 M) to pH 5.5, then extracted withethyl acetate (20 mL×3). The combined organic layers were washed withsaturated brine (50 mL), dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated in vacuo to remove the solvent. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=10/1) to give the title compound as a yellow solid (36 mg, 33%).

MS (ESI, pos. ion) m/z: 543.2 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 543.2513 [M+H]⁺, (C₃₀H₃₂FN₆O₃)[M+H]⁺theoretical value: 543.2520;

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 12.24 (s, 1H), 8.65 (s, 1H), 8.36 (s,1H), 8.29 (s, 1H), 8.01 (s, 2H), 7.33 (s, 1H), 7.09 (d, J=7.9 Hz, 2H),6.67 (s, 1H), 4.63 (s, 1H), 4.03 (d, J=7.0 Hz, 1H), 3.77 (s, 4H), 3.60(s, 1H), 3.24 (s, 4H), 1.93-1.29 (m, 10H).

Example 80:(+/−)-trans-3-((2-(5-fluoro-6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Step 1: 3-bromo-5-fluoro-6-methylpyridin-2-amine

To a solution of 5-fluoro-6-methylpyridin-2-amine (1.55 g, 12.3 mmol) inacetonitrile (16 mL) was added NBS (2.83 g, 15.9 mmol) in portions at−5° C. After the addition, the mixture was stirred at −5° C. for 1.5 h.To the mixture was added ethyl acetate (80 mL), and the resultingmixture was washed with water (80 mL) and saturated brine (80 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=10/1-3/1) to give the titlecompound as a light yellow solid (1.72 g, 68%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.41 (d, J=7.9 Hz, 1H), 4.78 (s, 2H),2.34 (d, J=2.9 Hz, 3H).

Step 2: 5-fluoro-6-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine

To a two-neck flask were added 3-bromo-5-fluoro-6-methylpyridin-2-amine(1.50 g, 7.32 mmol), bis(triphenylphosphine)palladium(II) chloride (513mg, 0.73 mmol), cuprous iodide (263 mg, 1.38 mmol), triethylamine (6.0mL, 43.2 mmol) and tetrahydrofuran (1.0 mL). To the mixture was addeddropwise slowly trimethylsilylacetylene (1.95 mL, 13.8 mmol) at rt undernitrogen protection, and the resulting mixture was heated to 50° C. andstirred for 4 h. The reaction mixture was cooled to rt, and saturatedaqueous ammonium chloride (30 mL) was added. The resulting mixture wasextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with saturated aqueous sodium chloride (80 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=15/1-4/1) to give the title compound as a gray solid(1.30 g, 80%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.23 (d, J=9.1 Hz, 1H), 4.84 (s, 2H),2.37 (d, J=2.9 Hz, 3H), 0.28 (s, 9H).

Step 3: 5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a suspension of potassium tert-butoxide (855 mg, 7.62 mmol) in NMP(15 mL) was added5-fluoro-6-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.30 g,5.85 mmol) in portions at 50° C. After the addition, the mixture washeated to 80° C. under nitrogen protection and stirred for 3 h. Thereaction mixture was cooled to rt and TsCl (1.35 g, 7.08 mmol) was addedin portions into the reaction mixture. After the addition, the mixturewas stirred at 30° C. for 2 h. To the mixture was added water (40 mL),and the resulting mixture was filtered. The filter cake was purified bysilica gel column chromatography (PE/EtOAc (v/v)=20/1-6/1) to give thetitle compound as a white solid (820 mg, 46%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.11 (d, J=8.3 Hz, 2H), 7.70 (d, J=3.9Hz, 1H), 7.44 (d, J=9.3 Hz, 1H), 7.31 (s, 2H), 6.51 (d, J=4.0 Hz, 1H),2.61 (d, J=3.2 Hz, 3H), 2.40 (s, 3H).

Step 4: 3-bromo-5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

The solution of 5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (590mg, 1.94 mmol) in DMF (8 mL) was cooled to 0° C., and bromine (0.3 mL, 6mmol) was added dropwise slowly to the solution. After the addition, themixture was stirred at rt for 2 h. The mixture was added dropwise into asaturated aqueous sodium thiosulfate solution (30 mL), and the resultingmixture was extracted with EtOAc (30 mL×3). The combined organic phaseswere dried over anhydrous Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatograph (PE/EtOAc (v/v)=5/1) to give the title compound as ayellow solid (468 mg, 63%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.10 (d, J=8.3 Hz, 2H), 7.76 (s, 1H),7.41 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.1 Hz, 2H), 2.63 (d, J=3.2 Hz, 3H),2.41 (s, 3H).

Step 5:5-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

To a microwave tub were added3-bromo-5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (468 mg,1.23 mmol), bis(pinacolato)diboron (483 mg, 1.90 mmol), potassiumacetate (248 mg, 2.53 mmol), Pd(dppf)Cl₂ (95 mg, 0.13 mmol) and DME (5mL). The air in the mixture was removed by bubbling with nitrogen for 10min and then the mixture was stirred at 130° C. for 2 h with microwaveheating. The reaction mixture was filtered through a celit pad, and thefilter cake was washed with ethyl acetate (30 mL). The filtrate wasconcentrated in vacuo, and the residue was used for the next step without further purification.

MS (ESI, pos. ion) m/z: 431.1 [M+H]⁺.

Step 6: (+/−)-trans-methyl3-((2-(5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate

To a microwave tub were added5-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(187 mg, 0.26 mmol, 60%), (+/−)-trans-methyl3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(80 mg, 0.22 mmol), potassium carbonate (89 mg, 0.65 mmol), Pd(dppf)Cl₂(35 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL). The air inthe mixture was removed by bubbling with nitrogen for 10 min and themixture in sealed tub was stirred at 110° C. for 3 h. The mixture wasfiltered through a celite pad, and the filter cake was washed with ethylacetate (50 mL). The filtrate was washed with saturated brine (50 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (n-hexane/EtOAc (v/v)=2/1) to give the title compound asa yellow solid (77 mg, 56%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.64 (s, 1H), 8.57 (d, J=9.9 Hz, 1H),8.17 (d, J=8.2 Hz, 2H), 8.11 (d, J=6.8 Hz, 2H), 7.54 (dd, J=14.6, 7.0Hz, 3H), 7.39 (d, J=4.3 Hz, 1H), 7.31 (s, 1H), 6.73 (s, 1H), 5.18 (s,1H), 4.54 (s, 1H), 3.74 (s, 3H), 2.64 (d, J=3.0 Hz, 3H), 2.45 (d, J=4.8Hz, 1H), 2.40 (s, 3H), 2.10 (s, 1H), 1.99 (s, 1H), 1.92-1.62 (m, 8H).

Step 7:(+/−)-trans-3-((2-(5-fluoro-6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid

To a solution of (+/−)-trans-methyl3-((2-(5-fluoro-6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate(77 mg, 0.12 mmol) in THF/MeOH (v/v=1/1, 3 mL) was added aqueous sodiumhydroxide solution (4 M, 0.30 mL, 1.20 mmol). The mixture was stirred at30° C. overnight, then diluted with water (20 mL). The resulting mixturewas acidified with hydrochloric acid (1 M) to pH about 5.5, thenextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated in vacuo to removethe solvent. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=10/1) to give the title compound as ayellow solid (25 mg, 44%).

MS (ESI, pos. ion) m/z: 472.5 [M+H]⁺;

HRMS (ESI, pos. ion) m/z: 472.2156[M+H]⁺, (C₂₇H₂₇FN₅O₂)[M+H]⁺theoretical value: 472.2149;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.31 (s, 1H), 12.07 (s, 1H), 8.55(s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.10 (s, 2H), 7.60-7.38 (m, 4H), 6.76(s, 1H), 4.64 (s, 1H), 2.53 (d, J=2.5 Hz, 4H), 1.99 (s, 2H), 1.86-1.39(m, 8H).

EXAMPLES OF BIOLOGICAL ASSAY

Using parts of the compounds of the invention as examples, the inventorshave detected antiviral and cytotoxicity activities and pharmacokineticproperties of the compounds of the invention in the following examples.

Example A: Cytopathic Effect Assay (CPE Assay)

Detection of the inhibitory effect of the compound of the inventionagainst cytopathic effect (CPE) of virus H1N1 A/Weiss/43 on cellularlevel in vitro.

Scheme 1: MDCK cells (Madin-Daby canine kidney cells) were seeded in a384-well plate with 2000 cells per well and cultured at 37° C. and 5%CO₂ overnight. Next day, cell culture medium was replenished with freshmedium containing appropriate concentrations of test compounds and virusH1N1 A/Weiss/43 at an multiplicity of infection to yield 80-95% CPE (orthe titer was 1 TCID90/well). The top final concentration of the testcompounds were 100 μM and then diluted by 3-fold serially for a total of8 concentrations at 100 μM, 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41μM, 0.14 μM, 0.05 μM. The test condition of cytotoxicity test group wasthe same as described above, except that the cell culture medium ofcytotoxicity test group didn't contain influenza virus. A virus controlgroup without drug and a no virus infected cell control group withoutdrug were set at the same time. Each group was set in duplicate, andincubated at 37° C. under 5% CO₂ condition for 5 days. The cell activitywas detected by using CCK-8 kits, and the data were used for calculatingthe antiviral effect and cytotoxicity against virus-infected cell of thecompound. Data were analyzed by using GraphPad Prism software, and theCPE inhibition ratio and cell survival ratio were calculated. EC₅₀ andCC₅₀ values were obtained according to the curve fitting.

CPE inhibition ratio=[(abosorbance of dosing well−abosorbance of viruscontrol well)/(abosorbance of cell control well−abosorbance of viruscontrol well)]×100%

cell survival ratio=[(abosorbance of dosing well−abosorbance of mediumcontrol well)/(abosorbance of cell control well−abosorbance of mediumcontrol well)]×100%

Table 1 shows inhibitory activities of compounds of the inventionagainst influenza virus (A/Weiss/43 (H1N1))

TABLE 1 Example No. EC₅₀ (μM) Example 1 <0.05 Example 2 <0.05 Example 3<0.05 Example 4 <0.05 Example 6 <0.05

The assay shows that the compounds of the invention have goodanti-influenza virus activities.

Scheme 2: MDCK cells (Madin-Daby canine kidney cells) were seeded in a384-well plate with 2000 cells per well and cultured at 37° C. and 5%CO₂ overnight. Next day, cell culture medium was replenished with freshmedium containing appropriate concentrations of test compounds and virusH1N1 A/Weiss/43 at an multiplicity of infection to yield 80-95% CPE (orthe titer was 1 TCID90/well). The top final concentration of the testcompounds were 50 nM and then diluted by 3-fold serially for a total of8 concentrations at 50 nM, 16.67 nM, 5.56 nM, 1.85 nM, 0.62 nM, 0.21 nM,0.068 nM, 0.023 nM. The test condition of cytotoxicity test group wasthe same as described above, except that the cell culture medium ofcytotoxicity test group didn't contain influenza virus. A Virus controlgroup without drug and a no virus infected cell control group withoutdrug were set at the same time. Each group was set in duplicate, andincubated at 37° C. under 5% CO₂ condition for 5 days. The cell activitywas detected by using CCK-8 kits, and the data were used for calculatingthe antiviral effect and cytotoxicity against virus-infected cell of thecompound. Data were analyzed by using GraphPad Prism software, and theCPE inhibition ratio and cell survival ratio was calculated. EC₅₀ andCC₅₀ values were obtained according to the curve fitting.

CPE inhibition ratio=[(abosorbance of dosing well−abosorbance of viruscontrol well)/(abosorbance of cell control well−abosorbance of viruscontrol well)]×100%

cell survival ratio=[(abosorbance of dosing well−abosorbance of mediumcontrol well)/(abosorbance of cell control well−abosorbance of mediumcontrol well)]×100%

Table 2 shows inhibitory activities of compounds of the inventionagainst influenza virus (A/Weiss/43 (H1N1))

TABLE 2 Example Number EC₅₀ (nM) Example 4 0.20 Example 4a 0.17 Example9 0.066 Example 9a 0.039 Example 16 0.54 Example 17 0.54 Example 230.104 Example 24a 0.744 Example 25 0.26 Example 49 0.068 Example 540.261 Example 55 0.874 Example 65 0.66 Example 78 0.236

The assay shows that the compounds of the invention have goodanti-influenza virus activities.

Example B: Pharmacokinetic Evaluation after Administering a CertainAmount of the Compound of the Invention by Intravenous or Oral to Rats,Dogs or Monkeys

Pharmacokinetic characteristics of the compound of the invention and thecontrol compound VX-787 (also named JNJ-872, the structure as shownbelow) in SD rat, dog or monkey were evaluated. The compounds disclosedherein were administered in form of a saline solution containing 5%DMSO, 5% Kolliphor HS 15 and 90% Saline. For intravenous administration(iv), the animals were administered with a dose of 1 mg/kg, and bloodsamples (0.3 mL) were collected at the time points of 0.083, 0.25, 0.5,1.0, 2.0, 5.0, 7.0 and 24 h after drug administration, then each bloodsample was processed to separate plasma by centrifugation at 3000 rpm or4000 rpm for 10 minutes. For oral administration (po), the animals wereadministered with a dose of 5 mg/kg, and blood samples (0.3 mL) werecollected at the time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hafter drug administration, then each blood sample was processed toseparate plasma by centrifugation at 3000 rpm or 4000 rpm for 10minutes. Plasma samples were collected and stored at −20° C. or −70° C.until LC/MS/MS analysis.

The assay shows that the compounds of the invention have high exposurelevel and good absorption in animals in vivo, and the pharmacokineticproperties of the compounds of the invention have significantadvantages.

Table 3 shows pharmacokinetic data of the compounds of the invention invivo of SD rat

TABLE 3 Test Administration Dosage C_(max) AUC_(last) AUC_(INF) CL VssCompound route mg/kg T_(max) h ng/mL t_(1/2) h hr * ng/mL hr * ng/mL F %L/h/Kg L/Kg Control iv 1 0.083 2840 5.72 1180 1210 N/A 13.8  1.81 VX-787 po 5 0.333 1970 4.14 3510 3530 58.4 N/A N/A (racemization)Example 1 iv 1 0.083 5900 1.13 4960 5020 N/A 17.1  1.03  po 5 0.833 31301.48 10100 10600 42.1 N/A N/A Example 2 iv 1 0.083 4910 1.06 3440 3470N/A 24.5  1.26  po 5 0.417 4020 1.33 8080 8180 47.1 N/A N/A Example 4 iv1 0.083 5980 2.71 4540 4610 N/A 3.66 0.412 po 5 0.667 3480 2.97 1280012800 56.4 N/A N/A Example 9 iv 1 0.083 10900 1.52 7260 7350 N/A 5.860.551 po 5 0.5 5270 3.15 17400 17500 47.5 N/A N/A Example 17 iv 1 0.0834420 1.12 2510 2520 N/A 33.1  1.49  po 5 0.5 2660 0.911 8270 8360 66.4N/A N/A Example 18 iv 1 0.083 4470 4.37 3130 3190 N/A 5.3  0.598 po 5 21690 3.71 6840 6880 43.1 N/A N/A Example 61 iv 1 0.083 8540 0.542 40304050 N/A 4.17 0.585 po 5 1.5 2710 5.95 10400 10700 53.1 N/A N/A Example63 iv 1 0.083 4990 3.85 4710 4750 N/A 3.55 0.416 po 5 2 3280 3.59 1530015400 65   N/A N/A Example 65 iv 1 0.083 6830 0.965 5340 5360 N/A 3.130.168 po 5 0.417 7940 1.14 12000 12100 44.9 N/A N/A Example 68 iv 10.083 3750 2.01 2760 2880 N/A 5.86 0.551 po 5 0.417 2960 3.24 8310 833060.1 N/A N/A Example 73 iv 1 0.083 14800 1.41 24200 24800 N/A  0.6810.212 po 5 1.5 9300 5.58 50600 52800 42.6 N/A N/A Example 80 iv 1 0.0835630 1.53 3320 3380 N/A 24.7  1.5  po 5 0.833 3130 1.48 10100 10600 62.5N/A N/A Notes: Control compound -(+/−)-trans-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid (The specific synthetic procedure can be seen in patent WO2010148197); AUC_(last) - AUC of 0 to 24 h; AUC_(INF) - AUC of 0 toinfinite time.

Table 3 shows that C_(max), AUC_(last) and AUC_(INF) of the compounds ofthe invention in SD rat were higher than these of the compound VX-787for both intravenous administration and oral administration. Itindicates that the compounds of the invention have high exposure leveland good absorption in SD rat, and the pharmacokinetic properties of thecompounds of the invention is significantly better than the controlcompound VX-787.

Reference throughout this specification to “an embodiment,” “someembodiments,” “one embodiment”, “another example,” “an example,” “aspecific examples,” or “some examples,” means that a particular feature,structure, material, or characteristic described in connection with theembodiment or example is included in at least one embodiment or exampleof the present disclosure. Thus, the appearances of the phrases such as“in some embodiments,” “in one embodiment”, “in an embodiment”, “inanother example, “in an example,” “in a specific examples,” or “in someexamples,” in various places throughout this specification are notnecessarily referring to the same embodiment or example of the presentdisclosure. Furthermore, the particular features, structures, materials,or characteristics may be combined in any suitable manner in one or moreembodiments or examples.

Although explanatory embodiments have been shown and described, it wouldbe appreciated by those skilled in the art that the above embodimentscannot be construed to limit the present disclosure, and changes,alternatives, and modifications can be made in the embodiments withoutdeparting from spirit, principles and scope of the present disclosure.

1. A compound having Formula (I) or a stereoisomer, a tautomer, anN-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof,

wherein each R¹ and R³ is independently H, F, Cl, Br, CN, NO₂,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), OR^(b), —NR^(c)R^(d),R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄ alkylene,3- to 12-membered heterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 10-memberedheteroaryl or (5- to 10-membered heteroaryl)-C₁₋₄ alkylene, and whereineach of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkyl-C₁₋₄ alkylene, 3- to 12-membered heterocyclyl, (3- to12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 10-membered heteroaryl and (5- to 10-memberedheteroaryl)-C₁₋₄ alkylene is independently unsubstituted or substitutedwith one, two, three or four substituents independently selected from F,Cl, Br, CN, OR^(b), —NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆ haloalkyl,R^(b)O—C₁₋₄ alkylene or R^(d)R^(c)N—C₁₋₄ alkylene; n is 0, 1, 2 or 3;each R² is independently F, C₂₋₆ alkynyl, OR^(b), C₃₋₁₂ carbocyclyl,C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-membered heterocyclyl, (3- to12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 14-membered heteroaryl, (5- to 14-memberedheteroaryl)-C₁₋₄ alkylene; or two adjacent R², together with the atomsto which they are attached, form a C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring or or 5- to10-membered heteroaromatic ring, and wherein each of the C₂₋₆ alkynyl,C₃₋₁₂ carbocyclyl, C₃₋₁₂ carbocyclyl-C₁₋₄ alkylene, 3- to 12-memberedheterocyclyl, (3- to 12-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 14-membered heteroaryl, (5- to14-membered heteroaryl)-C₁₋₄ alkylene, C₃₋₁₂ carbocyclic ring, 3- to12-membered heterocyclic ring, C₆₋₁₀ aromatic ring and 5- to 10-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F; each R′ is independently F, Cl, Br, CN, NO₂, ═O, OR^(b),—NR^(c)R^(d), R^(b)O—C₁₋₄ alkylene, R^(d)R^(c)N—C₁₋₄ alkylene,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene, 3- to6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄ alkylene,C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-membered heteroaryl or (5-to 6-membered heteroaryl)-C₁₋₄ alkylene, and wherein each of the C₁₋₁₀alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkylene,3- to 6-membered heterocyclyl, (3- to 6-membered heterocyclyl)-C₁₋₄alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to 6-memberedheteroaryl and (5- to 6-membered heteroaryl)-C₁₋₄ alkylene isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, Br, CN, NO₂, OR^(b),—NR^(c)R^(d), C₁₋₆ alkyl, C₁₋₆ haloalkyl, R^(b)O—C₁₋₄ alkylene orR^(d)R^(c)N—C₁₋₄ alkylene; m is 1 or 2; X has one of the followingsub-formulae:

wherein R⁴ is H or C₁₋₆ alkyl, and wherein the C₁₋₆ alkyl is optionallysubstituted with one, two, three, or four U; each R⁵, R⁶, R⁷ and R⁸ isindependently H or C₁₋₆ alkyl; or R⁵ and R⁶, together with the carbonatom to which they are attached, form a C₃₋₈ cycloalkyl group, 3- to6-membered heterocyclic ring, C₆₋₁₀ aromatic ring or 5- to 10-memberedheteroaromatic ring; or R⁷ and R⁸, together with the nitrogen atom towhich they are attached, form a 3- to 6-membered heterocyclic ring or 5-to 10-membered heteroaromatic ring, and wherein each C₁₋₆ alkyl, C₃₋₈cycloalkyl, 3- to 6-membered heterocyclic ring, C₆₋₁₀ aromatic ring or5- to 10-membered heteroaromatic ring is independently unsubstituted orsubstituted with one, two, three, or four U; W is a C₃₋₁₂ carbocyclicring or 3- to 12-membered heterocyclic ring; each V and V′ isindependently a C₃₋₁₂ cycloalkane ring, 3- to 12-membered heterocyclicring, C₆₋₁₀ aromatic ring or 5- to 10-membered heteroaromatic ring; eachR^(w) is independently F, Cl, Br, CN, NO₂, ═O, —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e), —S(═O)₂NR^(c)C(═O)R^(a),—S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂ alkylene, OR^(b), —NR^(c)R^(d),R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂ alkylene, C₁₋₆ alkyl, 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl, and wherein eachof the C₁₋₆ alkyl, 5- to 6-membered heteroaryl or 5- to 6-memberedheterocyclyl is independently unsubstituted or substituted with one,two, three, or four U; each U is independently F, Cl, Br, NO₂, CN, ═O,N₃, OR^(b), —NR^(c)R^(d), C₁₋₆ alkyl or C₁₋₆ haloalkyl; each s and t isindependently 0, 1, 2 or 3; p is 1, 2 or 3; and each R^(a), R^(b),R^(c), R^(d) and R^(e) is independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkylene, 3- to 6-membered heterocyclyl, (3- to 6-memberedheterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkylene, 5- to10-membered heteroaryl, (5- to 10-membered heteroaryl)-C₁₋₄ alkylene; orR^(c) and R^(d), together with the nitrogen atom to which they areattached, form a 3- to 6-membered heterocyclic ring, and wherein each ofthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkylene, 3- to 6-membered heterocyclyl, (3- to6-membered heterocyclyl)-C₁₋₄ alkylene, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄alkylene, 5- to 10-membered heteroaryl, (5- to 10-memberedheteroaryl)-C₁₋₄ alkylene and 3- to 6-membered heterocyclic ring isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, CN, OH, NH₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy or C₁₋₆ alkylamino.
 2. The compound of claim1 having Formula (II),

wherein A is a C₃₋₁₂ carbocyclic ring, 3- to 12-membered heterocyclicring, C₆₋₁₀ aromatic ring or 5- to 10-membered heteroaromatic ring; andq is 0, 1, 2, 3, 4 or
 5. 3. The compound of claim 1, wherein each R¹ andR³ is independently H, F, Cl, —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), OR^(b), —NR^(c)R^(d), C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, andwherein each of the C₁₋₃ alkyl, C₃₋₆ cycloalkyl, 5- to 6-memberedheterocyclyl, phenyl or 5- to 6-membered heteroaryl is independentlyunsubstituted or substituted with one, two, three or four substituentsindependently selected from F, Cl, OR^(b), —NR^(c)R^(d), C₁₋₃ alkyl,C₁₋₃ haloalkyl or R^(b)O—C₁₋₂ alkylene.
 4. The compound of claim 1,wherein each R² is independently F, C₂₋₆ alkynyl, OR^(b), C₃₋₆carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene; or two adjacent R², together withthe atoms to which they are attached, form a C₅₋₆ carbocyclic ring, 5-to 6-membered heterocyclic ring, benzene ring or 5- to 6-memberedheteroaromatic ring, and wherein each of the C₂₋₆ alkynyl, C₃₋₆carbocyclyl, C₃₋₆ carbocyclyl-C₁₋₂ alkylene, 5- to 6-memberedheterocyclyl, (5- to 6-membered heterocyclyl)-C₁₋₂ alkylene, phenyl,naphthyl, phenyl-C₁₋₂ alkylene, 5- to 6-membered heteroaryl, (5- to6-membered heteroaryl)-C₁₋₂ alkylene, C₅₋₆ carbocyclic ring, 5- to6-membered heterocyclic ring, benzene ring and 5- to 6-memberedheteroaromatic ring is independently unsubstituted or substituted withone, two, three, four or five R′, with the proviso that when m is 1, R²is not F.
 5. The compound of claim 1, wherein each R′ is independentlyF, Cl, Br, CN, N₀₂, OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)NR^(c)R^(d), C₁₋₉ alkyl, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, 5- to6-membered heterocyclyl, phenyl, phenyl-C₁₋₂ alkylene or 5- to6-membered heteroaryl, and wherein each of the C₁₋₉ alkyl, C₁₋₃haloalkyl, C₃₋₆ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene and 5- to 6-membered heteroaryl is independentlyunsubstituted or substituted with one, two, three, or four substituentsindependently selected from F, Cl, Br, CN, NO₂, OR^(b), —NR^(c)R^(d),methyl, ethyl, n-propyl or i-propyl.
 6. The compound of claim 1, whereineach R^(a), R^(b), R^(c), R^(d) and R^(e) is independently H, methyl,ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, 3- to 6-memberedheterocyclyl, phenyl, phenyl-C₁₋₂ alkylene; or R^(c) and R^(d), togetherwith the nitrogen atom to which they are attached, form a 5- to6-membered heterocyclic ring, and wherein each of methyl, ethyl,i-propyl, n-propyl, n-butyl, t-butyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, 3- to 6-membered heterocyclyl, phenyl,phenyl-C₁₋₂ alkylene and 5- to 6-membered heterocyclic ring isindependently unsubstituted or substituted with one, two, three, or foursubstituents independently selected from F, Cl, CN, OH, NH₂, C₁₋₃ alkyl,C₁₋₃ haloalkyl or methoxy.
 7. The compound of claim 1, wherein X has oneof the following sub-formulae:

wherein W is a C₆₋₈ carbocyclic ring or 6- to 8-membered heterocyclicring; each V and V′ is independently a C₃₋₈ cycloalkane ring, 3- to8-membered heterocyclic ring, benzene ring or 5- to 6-memberedheteroaromatic ring; each R^(w) is independently F, Cl, Br, CN, NO₂, ═O,—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —S(═O)₂R^(e),—S(═O)₂NR^(c)C(═O)R^(a), —S(═O)₂NR^(c)R^(d), (R^(b)O)₂P(═O)—C₀₋₂alkylene, OR^(b), —NR^(c)R^(d), R^(b)O—C₁₋₂ alkylene, R^(d)R^(c)N—C₁₋₂alkylene, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolylor pyrazolyl, and wherein each of methyl, ethyl, i-propyl, n-propyl,n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted orsubstituted with one, two, three, or four U; and each U is independentlyF, Cl, Br, CF₃, NO₂, CN, ═O, N₃, OR^(b), —NR^(c)R^(d), methyl, ethyl,i-propyl, n-propyl, n-butyl or t-butyl.
 8. The compound of claim 2,wherein A is a C₅₋₆ carbocyclic ring, 5- to 6-membered heterocyclicring, benzene ring, naphthalene ring or 5- to 6-membered heteroaromaticring.
 9. The compound of claim 1, wherein each R² is independently F,ethynyl, propynyl, OR^(b), C₃₋₆ carbocyclyl, 5- to 6-memberedheterocyclyl, phenyl, naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl,benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl,quinolyl, isoquinolyl, phenoxthinyl,

and wherein each ethynyl, propynyl, C₃₋₆ carbocyclyl, 5- to 6-memberedheterocyclyl, phenyl, naphthyl, phenyl-C₁₋₂ alkylene, furyl, benzofuryl,pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl,benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl,quinolyl, isoquinolyl, phenoxthinyl,

independently unsubstituted or substituted with one, two, three, four orfive R′, with the proviso that when m is 1, R² is not F.
 10. Thecompound of claim 7, wherein X has one of the following sub-formulae:


11. The compound of claim 2, wherein A is a C₅₋₆ carbocyclic ring, 5- to6-membered heterocyclic ring, benzene, naphthalene, furan, benzofuran,pyrrole, pyridine, pyrazole, imidazole, benzoimidazole, triazole,tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene,benzothiphene, pyrazine, pyridazine, pyrimidine, indole, purine,quinoline or isoquinoline.
 12. The compound of claim 7 having Formula(III), (IV), (V), (VI), (VII) or (VIII),


13. The compound of claim 1 having one of the following structures:

or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, apharmaceutically acceptable salt or a prodrug thereof.
 14. Apharmaceutical composition comprising an effective amount of thecompound of claim 1, optionally, further comprising a pharmaceuticallyacceptable carrier, adjuvant, vehicle or a combination thereof. 15.(canceled)
 16. The pharmaceutical composition of claim 14 furthercomprising one or more therapeutic agents, and wherein the therapeuticagent is an anti-influenza virus agent or anti-influenza virus vaccine.17. The pharmaceutical composition of claim 16, wherein the therapeuticagent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir,laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol,ribavirin, stachyflin, ingavirin, fludase, CAS no. 1422050-75-6,JNJ-872, AL-794, an influenza vaccine or a combination thereof. 18-23.(canceled)
 24. A method of preventing, managing, treating or lessening adisorder or disease caused by a virus infection in a patient, comprisingadministering to the patient a therapeutically effective amount of thecompound of claim 1, wherein the virus infection is influenza virusinfection.
 25. (canceled)
 26. A method of inhibiting RNA polymerase ofinfluenza virus in a patient, comprising administering to the patient atherapeutically effective amount of the compound of claim
 1. 27. Amethod of preventing, managing, treating or lessening a disorder ordisease caused by a virus infection in a patient, comprisingadministering to the patient a therapeutically effective amount of thepharmaceutical composition of claim 14, wherein the virus infection isinfluenza virus infection.
 28. A method of inhibiting RNA polymerase ofinfluenza virus in a patient, comprising administering to the patient atherapeutically effective amount of the compound of the pharmaceuticalcomposition of claim 14.